Going forward, we will be writing new articles for our CCN blog at https://www.pathologyoutlines.com/ccnblog.html.
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Author: natpernickgmailcom
Curing cancer – Curative cancer treatment based on complexity theory
27 June 2022
Prior blog entries have been merged and updated to create a new blog entry, click here.
Curing cancer – Adult versus childhood cancer
29 April 2022
I have revised “Curing cancer – Adult versus childhood cancer’, see link This brief article compares cancer in adults to cancer in children and adolescents focusing on numbers of deaths, clinical (microscopic) types, survival rates, etiology (how they arise) and curative treatment. Click at https://lp.constantcontactpages.com/su/onz6IND to sign up for our monthly newsletter.
Curing Cancer – reductionism versus complexity
12 April 2022
I have updated my article: Curing cancer – Reductionism versus complexity. It begins:
In 1971, President Richard M. Nixon announced the beginning of the “war on cancer” in the United States. Fifty years later, despite massive government expenditures and testimonials that the war on cancer “did everything it was supposed to do”, cancer is still a leading cause of death with high mortality from cancer of the lung, colon, pancreas and breast.
Our war on cancer has failed because our basic approach to biology is wrong. Biologic thinking has traditionally relied on reductionism, the theory that the behavior of the whole is equal to the sum of the behavior of the parts. Based on this theory, sophisticated systems are presumed to be combinations of simpler systems that can be reduced to simpler parts; this implies that disease is due to flawed parts and treatment merely needs to identify and repair or destroy the damaged parts. Although logical and rational, reductionism does not accurately describe the functioning of complex systems, including human biology.
Rest of article, https://www.pathologyoutlines.com/ccnblog/reductionismvscomplexity.html
Letter to President Biden, September 2021
Dear President Biden,
This is a brief update on our Strategic plan to substantially reduce cancer deaths, recently revised at http://www.natpernick.com/StrategicPlanCuringCancer.html. It supports your goal of “ending cancer as we know it.”
First, it is important to have an ambitious plan that spells out our actual goals and what needs to be done, to “dare greatly”, particularly because we don’t know how to achieve them.
Second, we propose that reducing the high number of US cancer deaths is a management problem that requires that we optimize each step of cancer’s clinical pathway (prevention, early detection, treatment and failure to respond to treatment). We should not be searching for a “silver bullet” or “magic pill” or talking about “a world without cancer”.
Third, we should study and reduce cancer deaths that occur shortly after diagnosis, which may be due to damage to essential physiologic networks that can be normalized initially, with specific anticancer treatment administered later.
Fourth, we speculate that for each cancer type, even the most aggressive, there exists a combination of perhaps 8-10 therapies that individually may be only partially effective but together can be substantially effective. Effective combinations not only target the cancer cells but their surrounding microenvironment; systemic networks involving inflammation, the immune system and possibly hormones; germline variations and known patient risk factors.
Finally, we outline important therapeutic strategies, including:
– Treatment should focus on managing the malignancy to reduce death and disability, not eliminating every cancer cell.
– Consider achieving “marginal gains” at all steps of the disease process, which may increase possible treatment options and reduce a sense of futility.
– Aggressively enroll patients into clinical trials so physicians can learn and improve over time.
Please let me know who specifically can think “out of the box” or might otherwise be interested in assisting with any part of this effort – we have limited contacts at the NIH, NCI and FDA. Please click on the blog or newsletter links below to stay in touch.
Nat Pernick, M.D., President and Founder
PathologyOutlines.com, Inc.
Email: Nat@PathologyOutlines.com
Telephone: 248/646-0325
Website: www.PathologyOutlines.com (see header for social media links)
Directory webpage: https://www.pathologyoutlines.com/directory/nat-pernick
Curing Cancer Network:
* Strategic Plan – http://www.natpernick.com/StrategicPlanCuringCancer.html*
* American Code Against Cancer – http://www.natpernick.com/AmericanCodeAgainstCancer.html
* Blog – https://natpernickshealthblog.wordpress.com/
* Newsletter – https://lp.constantcontactpages.com/su/onz6IND
Video – Current version of Strategic Plan
12 September 2021
This 7 minute video summarizes the current version (September 2021) of our strategic plan to substantially reduce cancer deaths, see http://www.natpernick.com/StrategicPlanCuringCancer.html.
Note: to see the notes summarizing the video, click on SHOW MORE below the video when displayed on YouTube. To increase the speed, click on Settings, then Playback Speed.
Pancreatic cancer update
8 September 2021
This essay summarizes current knowledge about pancreatic cancer and recent updates to our pancreatic cancer treatment targets (1).
Pancreatic cancer is currently the #3 cause of US cancer deaths, after lung and colorectal cancer, with a projected 48,220 deaths in 2021 (2). However, it is projected to become #2 by 2030 (3), because pancreatic cancer deaths are slowly increasing and colorectal cancer deaths are markedly decreasing (4).
Overall, Americans have a 1.7% lifetime risk of pancreatic cancer (5).
Pancreatic cancer has a 5 year relative survival rate of only 10% (2) with minimal improvements since the mid-1970s, unlike other cancers. Most patients (52%) are diagnosed with metastatic disease and have a 5 year relative survival of only 3% (2). For the 11% of patients with locally confined disease, the 5 year survival is still only 39%. This is likely due to the early dissemination of premalignant cells, typically before malignancy can even be detected (6).
We recently reviewed attributable risk factors for pancreatic cancer to determine what percentage of cases are due to each risk factor (4). These risk factors often overlap and add up to more than 100%:
Random chronic stress / bad luck – 25-35%
Non O blood group – 17%
Excess weight – 15%
Cigarette smoking (tobacco) – 15%
Type 2 diabetes – 9%
Excessive alcohol use – 5%
Diet – 5%
Family history / germline – 2%
Chronic pancreatitis – 1%
A newly described risk factor that may account for many of the “random chronic stress” cases is variant anatomy of the biliary ductal system (7). The variant anatomy may distort the usual pressures in this ductal system, causing reflux of bile into the pancreas or reflux of pancreatic juices into the biliary system. This may cause inflammation and ultimately cancer (8), analogous to how gastric reflux can cause esophageal cancer (9, 10).
What would a successful treatment strategy look like for pancreatic cancer? We recently speculated that there exists a large combination of partially effective treatments against pancreatic cancer (perhaps 8-10) that will produce high rates of long term survival even though the individual treatments will not (11, 12). This is similar to childhood leukemia, in which 4-5 drugs produce curative treatment, but only when given together. We suggest using therapies based not just on targeting the cancer cells themselves but also targeting the cancer microenvironment, systemic chronic inflammation, hormones, immune system dysfunction, relevant germline variations and risk factors, both behavioral and non behavioral.
Cancer can be viewed as a multidimensional web of biological pathways. To sufficiently reduce its malignant properties, therapy needs to successfully damage multiple strands on the web, not just the strands dealing with cell growth.
These challenges remain:
- We must prove that a large combination of partially effective treatments against pancreatic cancer will produce high rates of long term survival, even though the individual treatments will not. Currently, this is just a theory.
- Even if our theory about large combinations of therapy is correct, more effective therapies need to be developed against the different aspects of the malignant process discussed above other than cell growth.
- Receiving large combinations of therapies is difficult for patients and often seems cruel, although our experience with childhood leukemia suggests that it can be made more tolerable (13).
- We may need to develop 30 or more partially effective therapies to choose from to get the 8-10 therapies that are substantially effective in combination. But even so, it will be difficult to determine which combination of drugs will be most effective and how to optimally administer them. If there are 30 partially effective drugs against pancreatic cancer, then there are 6 million combinations of 8 drugs (11). Using machine learning, cell lines and animal models may be helpful to determine which combinations should be tested using clinical trials (1).
- Our framework for thinking and talking about cancer must change. Adult cancers are due to marked changes in systemic networks, not to a single local problem, and so cannot be “fixed” with a single therapy. Thus, we should stop talking about cures due to “silver bullets”. In addition, particularly for adult cancers, we should focus on managing cancer to reduce related deaths and symptoms, not on removing all cancer cells from the body.
How you can help:
- Follow our Curing Cancer Blog at https://natpernickshealthblog.wordpress.com .
- Sign up for our Curing Cancer Network monthly newsletter by clicking at https://lp.constantcontactpages.com/su/onz6IND .
- Become an example to others of anti-cancer behavior. Read our American Code Against Cancer at http://www.natpernick.com/AmericanCodeAgainstCancer.html, decide what steps you can take to reduce your cancer risk and spread the word through your social networks.
- Contact me at Nat@PathologyOutlines.com with your suggestions or thoughts.
References:
1. Pancreas treatment targets – http://natpernick.com/Pancreatic%20Cancer%20Treatment%20Targets.html
2. Cancer Facts & Figures 2021, https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf
3. Rahib 2014, https://pubmed.ncbi.nlm.nih.gov/24840647
4. Pernick 2021, http://www.natpernick.com/PancreaticcancerFeb2021.html
5. SEER, https://seer.cancer.gov/statfacts/html/pancreas.html, accessed 1Sep21
6. Rhim 2012, https://pubmed.ncbi.nlm.nih.gov/22265420/
7. Muraki 2020, https://pubmed.ncbi.nlm.nih.gov/32336556/
8. Funabili 2009, https://pubmed.ncbi.nlm.nih.gov/18500533/
9. PathologyOutlines.com – GERD, https://www.pathologyoutlines.com/topic/esophagusreflux.html
10. PathologyOutlines.com – Barrett esophagus, https://www.pathologyoutlines.com/topic/esophagusBarrettsgeneral.html
11. Pernick, http://www.natpernick.com/StrategicPlanCuringCancer.html
12. Pernick, http://www.natpernick.com/CombinationsOfTherapy.html
13. Mukherjee, https://www.amazon.com/Emperor-All-Maladies-Biography-Cancer/dp/1439170916
14. NIH, https://progressreport.cancer.gov/end/mortality
15. Wikipedia – bile duct, https://en.wikipedia.org/wiki/Bile_duct
Updates to Strategic Plan to Substantially Reduce Cancer Deaths
27 August 2021
This essay summarizes theAugust 2021 version of our Strategic plan to substantially reduce cancer deaths, click here. The current version is here.
* First, it is important to have an ambitious plan that itemizes what needs to be done and what needs to be better understood. Our plan might fail. But it is important to “dare greatly” (“The Man in the Arena”, 1910, retrieved 27Aug21) and attempt to achieve our actual goals, even if we do not know precisely how to do so.
* Second, reducing the high number of US cancer deaths is a management problem that requires that we optimize each step of cancer’s clinical pathway (prevention, early detection, treatment and failure to respond to treatment). It is not primarily a problem of finding a “silver bullet” or “magic pill”.
* Third, we should study and reduce cancer deaths that occur shortly after diagnosis. These may be preventable if due to (a) overzealous treatment that does not adequately balance treatment side effects, (b) predictable infections or (c) damage to essential physiologic networks that can be normalized.
* Fourth, we speculate that for each cancer type, even the most aggressive, there exists a combination of perhaps 8-10 therapies that individually may be only partially effective but together can be substantially effective. Effective combinations not only target the cancer cells but their surrounding microenvironment; systemic networks involving inflammation, the immune system and possibly hormones; germline variations in DNA and known patient risk factors for this disease.
* Finally, we outline important therapeutic strategies, including:
– Treatment should focus on managing the malignancy to reduce death and disability, not eliminating every possible cancer cell.
– Consider achieving “marginal gains” at all steps of the disease process, which may increase possible treatment options and reduce a sense of futility.
– Therapy should be patient centered to the extent possible because patients may have markedly different therapeutic preferences.
– Aggressively enroll patients into clinical trials so physicians can learn and improve over time.
You can help:
* Follow our Curing Cancer Blog at https://natpernickshealthblog.wordpress.com/
* Sign up for our Curing Cancer Network monthly newsletter by clicking at
https://lp.constantcontactpages.com/su/onz6IND .
* Become an example to others of anti-cancer behavior. Read our American Code against Cancer at http://www.natpernick.com/AmericanCodeAgainstCancer.html, decide what steps you can take to reduce your cancer risk and spread the word through your social networks.
* Contact me with your thoughts and suggestions at Nat@PathologyOutlines.com.
Letter to President Biden
10 August 2021
Dear President Biden,
I am a pathologist who developed PathologyOutlines.com, a free online pathology textbook used regularly by pathologists worldwide.
Consistent with your goal of ending cancer as we know it, I have developed a strategic plan to substantially reduce cancer deaths from the current level of 600,000 per year to 100,000 per year, see http://www.natpernick.com/StrategicPlanCuringCancer.html .
Who do you know, in or outside government, who is willing to “think outside the box”, and focus on this long term goal and what we need to do to get there?
Unfortunately, most cancer physicians and scientists are focused on short term thinking – promoting their career and not ruffling too many feathers. They don’t want to take risks that may fail. In addition, too many scientists are wedded to reductionist thinking and focus on naive concepts such as “the cure” or “a world without cancer”. However, cancer is the result of intersecting webs of disturbed physiologic networks – we typically will need to cut many strands of the web to destroy its function – a few drugs will usually be inadequate to do that. We also need more ambitious prevention goals such as markedly reducing tobacco use and obesity and making dramatic changes to our diet if we want to substantially reduce cancer deaths.
Our work is moving forward with the help of a growing network of interested people, but the more people in our network, the better. I would appreciate your help, or that of your staff, in advancing this cause by identifying interested people to work with us.
We don’t need your money, but we do need your connections!
Please review and advise.
Updates to Strategic Plan
6 August 2021
We have updated our Strategic Plan to substantially reduce cancer deaths, click here. The current version is here.
There are three main changes. First, we propose that success in substantially reducing cancer deaths is essentially a management task, not a technological one. Second, we have broken down treatment related goals into specific tasks that can be assigned to individuals or groups. Third, the overall plan was “tightened up” and is shorter.
We have created a table listing malignant attributes associated with pancreatic adenocarcinoma, the most common type of pancreatic cancer, click here. We need to further refine this table by adding more attributes, by identifying more treatments that are at least partially effective against these attributes and by contacting individuals who might be interested in pursuing clinical studies testing therapies against these attributes.
We plan to create similar tables for lung and liver cancer, the other major aggressive malignancies. For colorectal, breast and prostate cancer, we have to separate out the specific types that are the major causes of cancer death since most cases have favorable survival. We plan to hire a research assistant to assist with these tasks.
We have met with public health experts at the State and County level to discuss reducing the cancer risk factors listed in the American Code against Cancer. Although public health agencies are currently overwhelmed by the COVID-19 pandemic, we plan to work with them to discuss how to achieve the ambitious behavioral changes necessary to markedly reduce cancer deaths. We may also sponsor high school science fairs or essay contests related to cancer.
You can help:
* Follow our Curing Cancer Blog at https://natpernickshealthblog.wordpress.com/ .
* Sign up for our Curing Cancer Network monthly newsletter by clicking at
https://lp.constantcontactpages.com/su/onz6IND .
* Become an example to others of anti-cancer behavior. Read our American Code against Cancer at http://www.natpernick.com/AmericanCodeAgainstCancer.html, decide what steps you can take to reduce your cancer risk and spread the word through your social networks.
* Tell any medical researchers you know about our current grants at
https://www.pathologyoutlines.com/grants.html .
* Contact me with your thoughts and suggestions at Nat@PathologyOutlines.com
Random Chronic Stress Is a Major Cause of Pancreatic Cancer
28 July 2021
Pancreatic cancer is a major cause of US cancer death. It has risk factors that are preventable, such as cigarette smoking, excess weight, type 2 diabetes, excessive alcohol use and diabetes (Pernick, How Pancreatic Cancer Arises Based on Complexity Theory, 2021). It also has risk factors that are not, such as having blood groups A, B or AB (i.e. not O). This abstract discusses random chronic stress or bad luck, another major cause of pancreatic cancer that is not preventable (Curing Cancer Blog – Part 7 – Random Chronic Stress), which is also a major cause of lung cancer in nonsmokers (Pernick, How Lung Cancer Arises, Based on Complexity Theory, 2021).
This subject was discussed in the abstract below, which was not accepted at a recent conference. Although disappointing, the advantage of this rejection is that I can publish it without any restrictions. The full paper is at http://www.natpernick.com/PancreaticcancerFeb2021.html. I welcome your comments to Nat@PathologyOutlines.com.
Random Chronic Stress Is a Major Cause of Pancreatic Cancer
Context
Pancreatic cancer is the third leading cause of US cancer death, projected to become #2 by 2030. Patients have a 5 year relative survival rate of only 10%. Unlike other cancers, there have been minimal improvements since the mid-1970s. Many cases have no apparent risk factors.
Design
We analyzed the population attributable fraction (PAF) of known risk factors and estimated the proportion due to random chronic stress / bad luck. We then analyzed possible mechanisms for the initiation of pancreatic malignancy.
Results
Random chronic stress accounts for 25-35% of US cases, calculated as 100% minus the PAF of known risk factors. It causes an estimated 2 cases per 100,000 people per year (age standardized), accounting for 13,360 age adjusted cases.
We define random chronic stress as seemingly random cellular “accidents” that cause network dysfunction, promoted by prolonged lifespans, that may propagate to surrounding networks and promote malignancy, including (a) DNA or related replication errors in noncancerous stem cells; (b) errors in how DNA is organized or modified by epigenetic events; (c) errors in the distribution of cell components during cell division; (d) failure to restore physical interactions between tissue components after cell division, such as contact inhibition and (e) immune system dysfunction that, for a particular patient, is ineffective at eliminating premalignant or malignant cells. The category of random chronic stress / bad luck may include cancer risk factors not yet discovered, too infrequent to achieve statistical significance or not clinically evident in a patient, such as chronic pancreatitis without symptoms or microscopic changes.,
Based on self-organized criticality, our cellular networks are poised at a critical state in which small disturbances rarely set off a cascade of changes in the initial network, with long periods in which minor changes accumulate with no apparent clinical or microscopic changes, followed by bursts of activity leading to obvious premalignant or malignant changes. In evolution, punctuated equilibrium acts similarly. This is in contrast to gradualism, or stepwise cancer progression, which is logical and predictable but does not accurately describe malignant progression or evolution.
In lung cancer, patients with no risk factors have superior survival compared to those with risk factors; for pancreatic cancer, this is true of nonsmokers vs. smokers, but data is otherwise limited.
Conclusion
Due to these baseline rates of pancreatic and lung cancer, new cancers will continue to arise and a “world without cancer” is not foreseeable.
Letter to President Joe Biden, July 2021
I emailed this letter earlier this month – to date, there has been no response:
Dear President Biden,
Please identify who I should talk to concerning your goal of “ending cancer as we know it”. To be successful, we need better management, beginning with a strategic plan similar to the one I have developed, see http://www.natpernick.com/StrategicPlanCuringCancer.html.
We need a challenging goal, such as reducing US cancer deaths from the current level of 600,000 per year to 100,000 per year.
We need to identify the knowledge gaps and focus on research to fill them.
We need to abandon outdated concepts, such as talking about “the cure” or “a world without cancer”. We need to stop considering single drugs adequate for treatment. We need to recognize that cancer is within all older adults and that our goal should be to hold it in check, not to eliminate every cancer cell.
We need to study and target systemic networks that nurture malignancy and develop treatments to push cancer cells into networks that are less hazardous.
We need ambitious goals for behavioral changes, such as reducing tobacco use to 5% of the population, excess weight to 10% of the population and ensuring that all Americans get regular medical examinations to detect early disease and to promote prevention.
We need to manage cancer, both within a single patient and in our American society. Focusing solely on technology as the answer is a mistake.
Please review and advise.
Nat Pernick, M.D.
Video – Strategic plan to substantially reduce cancer deaths
19 July 2021
This 3 minute video outlines our strategic plan to substantially reduce cancer deaths.
Video summary:
We need a strategic plan to substantially reduce cancer deaths.
• To focus our efforts, identify gaps in knowledge.
• Goal is to reduce annual cancer deaths from current 600K to 100K by 2030.
• It might fail – that may be why others have not attempted this, but I think we can make important progress towards this goal.
Two main aspects – prevention, combinations of treatment.
• Prevention: American Code Against Cancer – not controversial, find ways to better promote these activities (see http://www.natpernick.com/AmericanCod… ).
• Combinations of Treatment: New thesis – If we have 20+ partially effective therapies for a specific type of cancer, then some some subset, in combination, should be substantially effective, see: http://www.natpernick.com/Combination...
• Behavior of whole is greater than sum of behavior of parts.
• Target: primary tumor, also microenvironment, systemic networks.
• Compiling a list, see http://natpernick.com/Pancreatic%20Ca…
• Then start clinical trials, or other means of testing (animal models, cell cultures, computer simulations).
What do you think?
Email me your comments to Nat@PathologyOutlines.com
Links for more information:
Strategic plan (cancer papers are towards the end): http://www.natpernick.com/StrategicPl…
American Code Against Cancer: http://www.natpernick.com/AmericanCod…
Curing Cancer Network newsletter: https://lp.constantcontactpages.com/s...
Letter to Director, National Cancer Institute,
4 July 2021
Hi Dr. Sharpless,
I read your April 2021 talk to the American Association for Cancer Research (AACR), see http://www.natpernick.com/AACRSharplessApril2021.pdf, and am distributing it to my network.
In my view, reducing the high number of US cancer deaths is primarily a management problem to be solved by creating a strategic plan that identifies necessary management and medical / scientific tasks:
1. Our goal should be to reduce annual US cancer deaths from 600,000 currently to 100,000 by 2030, as discussed in our strategic plan, http://www.natpernick.com/StrategicPlanCuringCancer.html. Although your goal of reducing age-adjusted cancer death rates in half is rational, this is too abstract to resonate with the hundreds of millions of Americans who must feel compelled to act.
2. I believe that we can substantially increase survival for aggressive pancreatic, lung, colorectal and breast cancers by using large combinations of partially effective therapies targeting different malignant attributes. For each cancer histological type, we should identify 20-30 important malignant attributes and then identify or develop therapies with at least partial effectiveness for each attribute, see http://natpernick.com/Pancreatic%20Cancer%20Treatment%20Targets.html. Then, our oncologists and pharmacologists can find combinations of 8-10 of these therapies that will be substantially effective, http://www.natpernick.com/CombinationsOfTherapy.html. This proposal is based on complexity science – the behavior of the whole is greater than the behavior of the sum of the parts. We should also reduce the number of clinical studies using only single agents (after initial trials establish their efficacy) – we know that single agents typically cannot be successful because they cannot adequately damage the weblike nature of the malignant process.
3. To determine the malignant attributes of each cancer histological type, we need to identify systemic network disturbances that nurture the cancer, such as microenvironmental factors, inflammation, unicellular-type programming, dysfunctional immune systems and hormones. We also have to better understand cancer cell stability (“cancer attractors”, https://pubmed.ncbi.nlm.nih.gov/19595782) and how to disrupt it with therapies that move tumor cells into less hazardous networks, https://pubmed.ncbi.nlm.nih.gov/31921665.
4. We need to investigate and reduce cancer deaths occurring within 30-60 days of diagnosis. These deaths, when due to infections, treatment side effects or disruption to vital physiologic networks, are often preventable, http://www.natpernick.com/CuringCancerPart9.html. Some of these cases may be analogous to diabetic ketoacidosis – with proper management, the life threatening episode can be resolved and the underlying disease can then be managed.
5. Long term, we can reduce cancer deaths by 30-40% through prevention and improved screening. We must reduce tobacco use to 5% or less of the population, improve the American diet to be predominantly plant based, reduce excess weight from 60% to perhaps 10% of the population and ensure that all Americans get adequate medical care including regular examinations to promote prevention and detect early disease.
My training is in mathematics, computer science, pathology and law, http://www.natpernick.com/, but my management experience is in creating a free online textbook in 2001, now used by most pathologists in the English speaking world, https://www.pathologyoutlines.com/ and creating (last month) a worldwide directory of pathologists, https://www.pathologyoutlines.com/directory.
Please contact me or have one of your staff contact me regarding the next steps we can take together.
Nat Pernick, M.D.
Curing Cancer Network:
* Strategic Plan – http://www.natpernick.com/StrategicPlanCuringCancer.html
* American Code Against Cancer – http://www.natpernick.com/AmericanCodeAgainstCancer.html
* Blog – https://natpernickshealthblog.wordpress.com/
* Newsletter – https://lp.constantcontactpages.com/su/onz6IND
New ideas about cancer
4 July 2021
This essay lists my new or “not generally accepted” ideas about cancer:
How cancer arises
1. Complexity science is more important than reductionism. We cannot understand cancer through reductionist thinking, which states that life is just a sophisticated machine that can be analyzed by breaking everything down into smaller and smaller discrete parts. In fact, the behavior of the whole is greater than the sum of the behavior of the parts. This “extra behavior” is due to interactions between the parts, often described as emergent behavior, which is unpredictable and nonlinear (Pernick, The Laws of Complexity and Self-organization: A Framework for Understanding Neoplasia 2017).
2. It is important to assess cancer in terms of network activity. In textbooks, a biologic pathway is often depicted as an assembly line of activity, with a beginning and end that are connected. However, each pathway is affected by numerous other pathways, meaning that the overall function resembles a web of activity. This has several consequences for cancer, including (a) blocks to any pathway can be bypassed through other pathways on the web; (b) networks have generic features that are independent of the details; (c) understanding changes in network behavior may be more important than identifying mutations (Pernick, Curing Cancer – Part 4 – Principles of curative treatment, 2021).
3. Coordination of network activity is a basic physiologic mechanism disrupted by malignancy. Isolated network activity can be useful or destructive, depending on its context; for sophisticated processes to be successful, such as inflammation and embryogenesis, groups of networks must work together in a specific, prescribed manner (Pernick, How Pancreatic Cancer Arises, Based on Complexity Theory, 2021). This coordination also extends to ending patterns of network activity. Inflammation and embryogenesis both have features of malignancy but their physiologic triggers also initiate the process of their resolution. Risk factors associated with malignancy activate these same networks but through a non coordinated process that has no programmed pathway to turn them off.
4. Malignant change occurs through bursts of network activity, not through gradual change. Nature often does not operate through gradual and stepwise change. Both complexity science and the related theory of self-organized criticality (Bak, How Nature Works, 1999) describe how small changes occur slowly over years, often unnoticed, until a critical point arises in which they reorganize with a burst of activity causing enormous transformations. In cells, cancer risk factors or random events trigger different patterns of network activity that accumulate and ultimately burst into intermediate states (premalignant conditions) that often are identifiable microscopically, such as a colonic adenoma (polyp) but may be identifiable only as altered patterns of molecular or network expression (Pernick, Focusing on Preinvasive Neoplasia, 2018). These intermediate states may then undergo additional changes until they burst into overt malignancy (Pernick, Curing Cancer – Part 7 – Random chronic stress / bad luck as a major cause of cancer, 2021).
5. Cancer is an inevitable tradeoff of human biologic design. Cancer will always be with us, particularly as life expectancy increases. New cancer cases will continue to arise due to random chronic stress and behavior which promotes cancer (e.g. tobacco use, excess weight) which cannot be totally eliminated (Pernick, Strategic Plan to Reduce Cancer Deaths, accessed 4 July 2021). However, we can often prevent it, we can detect it earlier and we can treat it more effectively (Pernick, How Cancer Arises Based On Complexity Theory, 2017).
6. Chronic cellular stress is the underlying cause of most cancers. Chronic cellular stress disturbs the delicate balance that exists in our interconnected cellular networks between stimulating and dampening forces. In the correct context, it pushes susceptible stem or progenitor cells into increasingly dysregulated and unstable network trajectories that propagate throughout the cell, across adjacent tissues and systemically (Pernick, The Laws of Complexity and Self-Organization: A framework for understanding neoplasia, 2011). Ultimately, it may produce a cancer attractor, which is a cell with malignant properties that has mutually regulating genes that create a network stability that is difficult to disrupt. It is foreseeable that some chronic cellular stressors will cause cancer but which stressors will be important, where the cancers will arise and what their molecular and microscopic features will be is not predictable (Pernick, How Cancer Arises Based On Complexity Theory, 2017).
7. Five “superpromoters” cause most adult cancers. We initially identified nine chronic cellular stressors as the major cause of cancer: chronic inflammation (due to infection, infestation, autoimmune disorders, trauma, obesity and other causes), exposure to carcinogens; reproductive hormones; Western diet (high fat, low fiber, low consumption of vegetables and fruit); aging; radiation; immune system dysfunction; germ line changes and random chronic stress / bad luck (Pernick, How Cancer Arises Based On Complexity Theory, 2017). Recently, we condensed this list to 5 “superpromoters”: chronic inflammation, DNA alterations (somatic or germline) / network rewiring, random chronic stress or bad luck, immune system dysfunction (individual or societal) and hormonal effects (Pernick, How Pancreatic Cancer Arises, Based on Complexity Theory, 2021). Chronic inflammation includes components of diet, aging and carcinogen exposure. The DNA alterations / network rewiring category includes carcinogen exposure, radiation, germline changes and a component of aging.
8. Random chronic stress or bad luck is a major cause of cancer death. This is particularly true for nonsmokers who develop lung cancer (Pernick, How Lung Cancer Arises, Based on Complexity Theory, 2021) or pancreatic cancer (Pernick, How Pancreatic Cancer Arises, Based on Complexity Theory, 2021). We propose that random chronic stress causes baseline rates of 2 cases per 100,000 people per year in the US for both lung and pancreatic cancer (Pernick, Curing Cancer – Part 7 – Random chronic stress / bad luck as a major cause of cancer, 2021).
9. Cancer arises due to numerous changes in the immune system that evolve during the entire malignant process. Targeting one aberrant pathway in the immune system is unlikely to be effective because it, like cell growth pathways, operates as a biologic web (Pernick, How Pancreatic Cancer Arises, Based on Complexity Theory, 2021). In addition, a “runaway” immune system may play a prominent role in malignancies with no known risk factors such as classical Hodgkin lymphoma, nodular lymphocyte predominant Hodgkin lymphoma and glioblastoma (Pernick, How cancer arises from chronic inflammation, based on complexity theory, 2020).
Treatment strategies
10. We need a strategic plan to substantially reduce cancer deaths. Complexity theory recognizes that countering systemic diseases requires optimizing all factors affecting it, even if not directly part of the malignant process. Relying on a “silver bullet” or single solution is unlikely to be effective (Pernick, Strategic Plan to Reduce Cancer Deaths, accessed 4 July 2021). Our goal is to reduce annual US cancer deaths from 600,000 in 2021 to 100,000 by 2030. However, successful implementation requires that we focus on all important aspects of cancer, regularly track our progress and update the plan as needed.
11. Cancer deaths cannot be reduced to zero. Even with optimal treatment for a specific type of cancer, some patients will still die of cancer because of treatment refusal, compliance issues, medical conditions which interfere with treatment, treatment error, treatment failure for unknown reasons and development of additional cancers (Pernick, Strategic Plan to Reduce Cancer Deaths, accessed 4 July 2021).
12. Successful cancer treatment requires combinations of drugs or other therapies because the malignant process constitutes a biologic web that has many pathways to bypass a specific block. This web consists of networks associated with the cancer cells themselves, their microenvironment (surrounding tissues) and the systemic networks (including chronic inflammation, immune system, hormones) that support them.
13. For each cancer histological type, we should identify 20-30 important malignant attributes and then identify or develop therapies with at least some effect for each attribute. We have developed an initial list for pancreatic cancer, see Pancreatic Cancer Treatment Targets. Much work remains for investigators to find partially effective therapy directed against some of these malignant traits.
14. We propose that our oncologists and pharmacologists can find combinations of 8-10 partially effective therapies against aggressive cancers that, as a combination, will be substantially effective (Pernick, Combinations of therapy to subsantially reduce cancer deaths, 2021). The combinations, considered as a whole, will have behavior much greater than the sum of the behavior of the individual treatments.
15. To have the greatest impact on reducing cancer deaths, we should focus on treatments for lung and pancreatic cancer and advanced cancers of the colon and breast, which cause the largest number of cancer deaths. It may be difficult to target all cancer attributes because patients can only tolerate a limited number of therapies. Determining which combinations of therapies work together will require more aggressive enrollment of patients into clinical trials so physicians can learn and improve as much as possible.
16. New therapies to be developed include: targeting networks, not just mutations; moving cancer cells that survive treatment into less dangerous pathways; attacking the microenvironment that nurtures the cancer; and identifying, monitoring and targeting systemic networks affecting the cancer. To be successful, we need to target as many aspects of the malignant process as possible.
17. It is important to study and reduce cancer deaths that occur soon after diagnosis due to treatment side effects, infections or life threatening disruptions to essential physiologic networks (Pernick, Curing Cancer blog – part 9 – How cancer kills, 2021). It is also important to reduce cancer deaths due to a sense of futility which are based on expectations that may not be reasonable.
Public health / prevention strategies
18. It is important to strengthen public health and preventative programs to promote a culture of being healthy and reducing risky behavior. This includes promoting the American Code Against Cancer and other healthy lifestyle messages. At a societal level, our public health and medical care systems act as a “behavioral immune system” to reduce cancer risk factors and the incidence of cancer (Pernick, How Pancreatic Cancer Arises, Based on Complexity Theory, 2021). Nonuse of screening is a major cause of cancer death (Pernick, How colorectal cancer arises and treatment approaches, based on complexity theory, 2020).
19. Long term, we can reduce cancer deaths by 30-40% through prevention and improved screening. We must reduce tobacco use to 5% or less of the population, improve diets to be predominantly plant based, reduce excess weight from 60% to perhaps 10% of the population and ensure that all Americans get adequate medical care including regular examinations to promote prevention and detect early disease.
20. We should focus on improving screening programs that will reduce the most cancer deaths. This includes screening for cancers with high mortality but effective treatment options when detected early; identifying premalignant or malignant lesions in both high risk patients and current cancer patients being monitored for relapse and identifying the most important screening programs for patients with cancer at risk for second cancers. We should also analyze whether testing or treatment for chronic inflammation associated with cancer is useful and if so, how best to do it.
21. It is important to improve access to medical care. We should determine the most effective types of medical intervention to reduce cancer deaths and how best to provide this care to needed patient populations.
22. It is important to promote collaboration between physicians and scientists to create successful treatment combinations and change public policy to improve cancer screening and prevention. Physicians and scientists must work together to exchange knowledge and develop treatments that combine their experience and expertise.
Combinations of therapy to substantially reduce cancer deaths
23 June 2021
Our strategic plan aims to reduce annual US cancer deaths from 600,000 projected in 2021 to 100,000 by 2030. The war on cancer, now 50 years old, needs a specific goal and time frame to focus our efforts. This echoes the challenge in 1961 from President John F. Kennedy to land a man on the moon by the end of that decade (President Kennedy Challenges NASA to Go to the Moon, 1961 at 1:09).
The “moonshot” is often used as an inspiration to utilize our collective brainpower and other talents to find a “cure” for cancer:
The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal. President Nixon’s 1971 State of the Union at 15:03.
Successful cancer treatment may be analogous to the moon landing, but only if we consider that the moon landing was due not to a single breakthrough, but combinations of technological and scientific advances related to all aspects of the flight. Similarly, success at reducing cancer deaths will require a range of therapies directed at all aspects of the malignant process, as well as efforts to reduce risk factor exposure and improve screening.
This essay introduces our strategy of using combinations of therapies directed at all aspects of the malignant process, appropriate for each cancer type, to substantially reduce cancer related deaths. This strategy is based on the understanding that cancer is the result of intersecting webs of biological activity for the cancer cells, their microenvironment and systemic networks affecting the cancer. Effective treatment must damage the end result of these webs sufficiently so that their overall malignant properties cannot continue. This typically cannot be achieved by a single drug, for several reasons. First, one drug may break only one strand of one web and can be readily bypassed through alternative pathways. For example, childhood cancers have an uncomplicated origin due to inherited or constitutional cancer predisposition or developmental mutations that may only activate a single pathway. Yet single drug treatment for childhood leukemia invariably fails – it initially kills most cancer cells but they return through activation of alternative pathways. Successful therapy requires combinations of 3-5 drugs with different mechanisms of action (Curing Cancer Blog – Part 2 – Adult versus childhood cancer, 2020). Second, adult cancers have a complicated origin because they originate from mutations in many cells caused by multiple risk factors acting over long periods. Thus, adult cancers need additional combinations of treatment that target the more diverse primary cancer, the cancer cell microenvironment and the systemic networks that nurture and promote cancer growth.
For each specific cancer type, we propose that successful treatment is possible using combinations of therapies with some demonstrated impact on the attributes of the malignant process listed below. Although no therapy may individually eradicate the cancer, combinations of these partially effective therapies may damage the related biologic webs sufficiently to lead to prolonged patient survival. Subsequently, we can refine these preliminary successes to further improve survival and reduce side effects (see Curing Cancer Blog – What will success look like in the war on cancer? 2021). We propose creating a summary for each cancer type of its cancer related attributes and known therapies for use by oncologists to create combinations to test – click here for the current summary for pancreatic adenocarcinoma.
These are the general malignant attributes to target, which must be refined for each cancer type:
Malignant attributes of the primary cancer, including rapid cell growth, cell migration, resistance to apoptosis, immature phenotypes; driver mutations and their networks, networks promoting unicellular type programming; resistance to disruptions to their cancer attractor states that prevent changes to their malignant phenotypes.
Features of the microenvironment that sustain the cancer, including inflammation, vasculature, stroma and the extracellular matrix.
Associated systemic networks which promote cancer growth, including chronic inflammation, immune system dysfunction and hormonal production (estrogens, androgens and insulin) (Curing Cancer Blog – Part 8 – Strategic Plan, 2021).
Germline variations of genes promoting the above features.
Patients can only tolerate a limited number of therapies at one time. Determining which combinations of therapies work optimally together and how to administer them will require extensive clinical trials, although deep learning and other computational approaches may be helpful (How Pancreatic Cancer Arises, Based on Complexity Theory, 2021).
We also need to better understand, treat and minimize cancer deaths occurring shortly after diagnosis, whether due to treatment side effects, infections or severe disruptions to important physiologic systems (Curing Cancer blog – part 9 – How cancer kills, 2021).
To improve survival for cancer types typically associated with longer survival, we should also promote behavior changes in patients to reduce risk factors for additional cancers. To reduce the incidence of cancer in general and promote better patient care, we need to optimize our public health system. A well run public health system acts as a behavioral immune system to prevent many lethal cancers from arising through risk factor reduction and earlier detection (How Pancreatic Cancer Arises, Based on Complexity Theory, 2021). It also optimizes patient health through equitable and adequate access to medical care.
To have the greatest impact on reducing cancer deaths, we should initially focus on lung cancer, pancreatic cancer and advanced cancers of the colon and breast, which are the leading causes of US cancer death (Curing Cancer blog – What will success look like in the war on cancer? 2021).
This strategic plan focuses on the common goal of physicians and scientists worldwide to substantially reduce cancer deaths. Its implementation will take continued hard work, the ability to admit our failures and learn from them and the need to overcome the limitations of institutional thinking. But we can succeed:
“We choose to go to the moon. We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard, because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win, and the others, too. (“Why go to the moon?” – John F. Kennedy at Rice University, at 9:38).
What will success look like in the war on cancer?
11 June 2021
What will success look like in the war on cancer? When we begin with the end in mind, it helps us focus on what we want to achieve, understand better how this success can be attained and create processes to do so. The goal of our strategic plan is to reduce US cancer deaths from the present 600,000 per year to 100,000 per year by 2030. But how will this happen?
Historically, medical success has three phases. First, there is a long period of increasingly greater understanding of the disease and discovery of new treatments and prevention measures but with a limited improvement in death rates. Later, refinement and coordination of these new treatments and a better understanding of prevention measures cause dramatic improvements in the death rate. Finally, with treatment largely successful and prevention more effective, there are only small improvements in the death rate and a focus on reducing the side effects of treatment.
Our success in treating HIV / AIDS illustrates these three phases. The blue line below shows increasing deaths from 1981 (when it was first discovered) to 1995, followed by a dramatic drop in deaths through 1997, followed by a small decline, see MMWR 2011. Of note, the drop in deaths is due not only to improved treatment, but also to a reduced incidence of HIV / AIDS due to more effective prevention activities. Without treatment, most patients die within 10-15 years from exposure (Lancet 2000).
For childhood leukemia, there were also three phases in treatment success, as shown by the graph below of deaths in England and Wales, see Shaw 2007. The death rate increased until the early 1960’s when the relative 5 year survival was close to zero, then decreased dramatically until the late 1990’s when the relative 5 year survival rate was 70-80%, and has since flattened out. For childhood leukemia, there is no known cause or prevention strategy. Incidence has risen slightly, for unknown reasons.
For cancer in the United States, the leading causes of death are lung cancer, colorectal cancer, pancreatic cancer and breast cancer, which together account for 277,210 (45.6%) of the 608,570 projected cancer deaths in 2021. To reach our goal of only 100,000 annual deaths, there will need to be major reductions in the cancer death rates at these sites.
Deaths in 2021 (projected) and 5 year relative survival
| 1 | Lung cancer | 131,880 | 21% |
| 2 | Colon cancer | 52,980 | 65% |
| 3 | Pancreatic cancer | 48,220 | 10% |
| 4 | Breast cancer | 44,130 | 90% |
| 5 | Prostate cancer | 34,130 | 98% |
| 6 | Liver cancer | 30,230 | 20% |
| 7 | Leukemia, including AML | 23,660 | 64% |
| 8 | Non Hodgkin lymphoma | 20,720 | 73% |
| 9 | CNS tumors | 18,600 | 33% |
| 10 | Bladder cancer | 17,200 | 77% |
| 11 | Esophageal cancer | 15,530 | 20% |
| 12 | Kidney cancer | 13,780 | 75% |
| 13 | Ovarian cancer | 13,770 | 49% |
| 14 | Uterine cancer | 12,940 | 81% |
| 15 | Myeloma | 12,410 | 54% |
| 16 | Skin | 11,540 | 93% (melanoma) |
| 17 | Stomach | 11,180 | 32% |
| 18 | Oral cavity & pharynx | 10,850 | 66% |
| 19 | Soft tissue | 5,350 | 65% (a) |
| 20 | Gallbladder | 4,310 | 19% (b) |
Sources: Cancer Facts & Figures 2021, Tables 1, 7 and 8, (a) Cancer.org, (b) Cancer.org.
For the past 70 years we have been slowly accumulating new knowledge with small improvements in treatment and minor reductions in overall cancer deaths, but at some point, these improvements will coalesce into substantial reductions. Our strategic plan focuses on reducing gaps in important knowledge and increasing collaboration of research activities to get to the “dramatic improvement” phase.
Other processes, including the development of cancer, also follow these three phases. During the malignant process, our cellular networks slowly accumulate minor variations with no apparent clinical or microscopic changes. This is followed by bursts of activity leading to obvious premalignant or malignant changes (Cross 2016). Once malignant, the cancer may become more aggressive (dedifferentiation) or accumulate only minor changes. Similarly, in evolution, the theory of punctuated equilibrium describes prolonged periods of apparent stasis (i.e. no new species) followed by bursts of new species (Eldredge & Gould 1972). During the “quiet” periods and after the “burst” phase, minor changes in the genetic code are accumulating, albeit without being noticed.
The theory of self-organized criticality, which also describes earthquakes and stock market crashes, helps us understand these phases (Bak, How Nature Works 1999). Many systems, both biologic and sociological, are networks poised at a critical state in which small disturbances typically cause no network changes, occasionally cause small network changes and rarely set off a cascade of changes in the initial network and those it interacts with. By analogy, individual grains of sand dropped on a sandpile usually have no apparent impact, occasionally cause small avalanches and rarely cause the entire sandpile to collapse. Dropping a single grain of sand with no apparent impact causes small structural changes in the sandpile that ultimately may enable an additional grain to set off an avalanche. According to Kauffman, these “minor” changes build up connections between elements in the network until a “phase transition” occurs in which so many connections exist that the network elements act together as a whole, instead of as individual elements. When a large enough number of “reactions” are catalyzed, a vast web of reactions will suddenly crystallize and produce dramatic change (Kauffman, At Home in The Universe, page 58).
For cancer research, individual researchers typically study short segments of the “web” of activity that constitutes cancer. When enough segments are understood, and there are enough connections made between their work, we anticipate that this web of collaborations will produce an explosion of new ideas and more effective treatments.
In contrast, the theory of gradualism proposes that major changes occur due to the steady accumulation of small changes that produce visible differences. Gradualism is logical and predictable and was promoted by Darwin (Gould 1983), but it does not accurately describe evolution, malignant progression or the resolution of disease (Sun 2018).
The acceleration of prevention activities will also reduce cancer deaths, but this typically has a long lead time. For cigarette smoking, one of the most important preventable causes of cancer deaths, reductions in lung cancer deaths in men, only began 20 years after the groundbreaking Surgeon General’s Report on Smoking and Cancer.
Source: American Cancer Society
Knowing what success in the war on cancer is likely to look like, we can continue to emphasize the attainment and accumulation of small successes and collaboration between scientists, instead of relying on the discovery of a miracle drug or treatment.
The importance of systemic networks in cancer treatment
1 June 2021
Cancer is a systemic disease. This means it is important to treat not just the obvious tumor mass but also the systemic cellular networks that nurture the tumor. Surprisingly, most cancer treatment plans ignore the systemic networks.
Targeting systemic tumor networks will be difficult, requiring combinations of combinations of therapy. We will need different therapeutic strategies for the primary tumor and many of the systemic networks. Each type of therapy may need to consist of combinations of treatments to block a sufficient number of steps in the web-like pathways that exist for each cellular function.
This subject was discussed in the abstract below, which was not accepted at a recent conference. Although disappointing, the advantage of this rejection is that I can publish it now without any copyright restrictions. The full paper is at http://www.natpernick.com/PancreaticcancerFeb2021.html. Please send your comments to Nat@PathologyOutlines.com.
Monitoring Dysfunctional Networks To Support Curative Treatment of Pancreatic Cancer
March 2021
Nat Pernick, M.D., Nat@PathologyOutlines.com
Context: Pancreatic cancer is a systemic disease with dysfunctional networks that must be treated and monitored, in addition to the primary tumor.
Design: We calculated the population attribution fraction of pancreatic cancer risk factors and reviewed their mechanisms of action within the context of complexity theory to determine common features, principles of curative therapy and key network issues.
Results: Random chronic stress causes 25-35% of cases, non O blood group 17%, excess weight 15%, cigarette smoking 15%, type 2 diabetes 9%, alcohol 5%, diet 5%, family history / germline 2% and chronic pancreatitis 1% (Table 1). Risk factors can be categorized into 5 “super promoters”: chronic inflammation, DNA alterations, random chronic stress / bad luck, immune system dysfunction (individual or “societal”) and hormones. We identified key systemic network issues that curative therapy must address and propose monitoring their response to treatment: overall inflammatory process, immune system’s antitumor capabilities, microenvironment (vasculature, inflammation, fibroblasts, extracellular matrix) of tumor and metastatic sites, activation of unicellular-like networks, activation of embryonic networks, insulin-IGF system and germline networks that promote malignant behavior. Pathologists must create assessments of each key network’s response to treatment by determining relevant biomarkers to measure and understanding how their expression affects treatment and survival. Developing a cancer network score analogous to the TNM score may be useful.
Conclusions: Pancreatic cancer has an altered systems biology with changes in systemic, nontumor networks that typically will not revert to normal by destroying the original tumor. Curative therapy requires treatment targeting these networks and monitoring their response to treatment.
Table 1 – Pancreatic cancer risk factors
Risk factor Attributable fraction
Random chronic stress 25-35%
Non O blood group 17%
Excess weight 15%
Cigarette smoking 15%
Type 2 diabetes 9%
Alcohol use 5%
Diet 5%
Family history / germline 2%
Chronic pancreatitis 1%
Table 2 – Cancer “super promoters”
Chronic inflammation
DNA alterations
Random chronic stress / bad luck
Immune system dysfunction (individual or “societal”)
Hormones
Table 3 – Key systemic network issues
Overall inflammatory process
Immune system’s antitumor capabilities
Microenvironment (vasculature, inflammation, fibroblasts, extracellular matrix) of tumor and metastatic sites
Activation of unicellular-like networks
Activation of embryonic networks
Insulin-IGF system
Germline networks that promote malignant behavior
What should our national cancer goals be?
26 May 2021
What are reasonable goals regarding cancer in the United States?
First, let’s discuss what is not reasonable. Conquering cancer does not mean attaining “a world without cancer” (American Cancer Society Mission Statement, accessed 12May21). Cancer will always be part of our world. New cancer cases will continue to arise because (a) cancer is part of the tradeoff inherent in the design of multicellular organisms (Jacqueline 2016); (b) new cancers will continue to develop due to random chronic stress or bad luck (Curing Cancer Blog – Part 7 – Random chronic stress / bad luck as a major cause of cancer, 2021) and (c) we cannot completely eliminate personal behavior which promotes cancer, such as tobacco use or excess weight.
Second, cancer deaths cannot be reduced to zero. There are hundreds of types of cancer, considering that the same type of cancer at different body sites may be a different disease. Developing optimal treatment for all these diseases will take decades. Even if optimal treatment for a specific cancer is developed, some patients will still die of cancer because of treatment refusal, compliance issues, medical conditions which interfere with treatment, treatment error, treatment failure for unknown reasons and development of additional cancers.
Third, conquering cancer is not equivalent to splitting the atom or landing a man on the moon, as articulated in President Nixon’s announcement of the War on Cancer in 1971:
I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dreaded disease. Let us make a total national commitment to achieve this goal. President Nixon’s 1971 State of the Union at 15:03
Splitting the atom and landing on the moon were achieved by a concentrated effort among a select group of people. However, to markedly reduce cancer deaths will require changes in individual behavior by hundreds of millions of people, new government policies and a myriad of research breakthroughs.
Fourth, we must stop relying on an outdated view of biology that presumes that we can find a “silver bullet” to cure cancer. Scientific theory is often based on reductionism, a belief that the behavior of the whole is equal to the behavior of the sum of the parts. The reductionist goal for cancer was to find and fix the broken parts. In reliance on this theory, we focused on “the cause” and “the cure”. However, this way of thinking is incorrect.
Life and much of the physical world is actually based on complexity science: the behavior of the whole is greater than the sum of the behavior of the parts. These extra properties are due to interactions between the parts, which are often unpredictable and surprising. Each type of cancer is caused by behavioral risk factors or random events that cause small network changes beginning in a few cells that slowly percolate across adjoining networks and eventually may produce bursts of major changes leading to premalignant conditions. Additional bursts may cause overt cancer. Due to the complicated nature of these network changes, occurring over large areas of an organ or body site, no simple therapy can eradicate the existing cancer and premalignant conditions and restore order.
What can we do?
We can prevent many cases of cancer, we can detect them earlier and we can develop more effective treatment. We can, I believe, reduce annual US cancer deaths from the current 600,000 to 100,000, as discussed in our strategic plan. We cannot “cure” most cancers in the sense of ridding them completely from our lives, but we can “conquer cancer” or “end cancer as we know it” or make cancer just another chronic disease that we have to monitor and manage.
It is instructive to think about the types of cancer we have successfully treated, including childhood leukemia, testicular cancer and Hodgkin lymphoma. These cancers of children and young adults are easier to treat than adult cancers because they are typically caused by inherited or constitutional cancer predisposition or developmental mutations (Kentsis 2020), are not due to risk factors and show no “field effects” (large areas affected by premalignant or malignant change) (Curing Cancer, Part 2 – Adult versus childhood cancer, 2020). Even so, effective treatment is complicated. It involves detailed study of the cancers to classify them correctly, combinations of treatments that require sophisticated administration (Mukherjee: The Emperor of All Maladies 2010), careful attention to preventing and managing treatment side effects and enrolling as many patients as possible in clinical trials to learn from each patient’s experience (NCI: Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version, accessed 12May21).
Treating adult cancers is more difficult than treating childhood cancers. Adult cancers are caused by risk factors acting over decades, including tobacco use and exposure to other carcinogens, alcohol use, excess weight, Western diet (high fat, few vegetables), microorganisms and parasites, constant hormonal exposure and immune system dysfunction (Pernick 2017). Instead of combinations of treatments required for cancers in the young, combinations of combinations of treatments will be necessary to destroy a sufficient number of links on the weblike biologic pathways that nurture the cancer (Curing Cancer – Part 8 – Strategic plan for curing cancer, Feb 2021). No magic pill will eliminate these diseases.
Success in the war on cancer will require us to continually assess what we know and what we don’t know and to improve our strategic plan accordingly. For adult cancers, we must focus on the biologic networks of the primary cancer (for solid cancers) and its microenvironment, as well as systemic networks affecting the cancer (e.g. inflammation, some germline variations, immune system dysfunction, hormonal effects, risk factor related networks). We need a marked increase in clinical trials to test new therapies. We need national, state and local commitments for prevention to reduce risk factors causing cancer and to identify cancers earlier. Finally, we also need more individuals and institutions to be honest and admit that they don’t know everything and to acknowledge when they make mistakes so that we can continually improve on these difficult goals.
Let’s cure cancer together
Revised 28 April 2021
It’s time to implement a strategic plan to cure cancer.
The era of modern cancer treatment began in 1948, when Dr. Sidney Farber, a Boston pathologist, published a landmark study reporting that chemotherapy could induce temporary remissions in childhood leukemia (Farber 1948, free full text-PDF download). Remarkably, this study was met not with hope and acclaim, but with skepticism and outrage (Miller 2006).
In 1971, President Richard M. Nixon announced the beginning of the “war on cancer” in the United States (see President Nixon’s 1971 State of the Union at 15:03):
I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dreaded disease. Let us make a total national commitment to achieve this goal.
Yet 50 years later, cancer is still the #2 cause of death in the United States (after heart disease), causing a projected 608,570 deaths in 2021 (Cancer Facts & Figures 2021-PDF download). In high income countries as a group, cancer is the #1 cause of death (Dagenais 2020).
Total US cancer deaths have only recently started to plateau, but still at a very high level (references):
Although US cancer death rates by population have been declining since 1990 (due primarily to reductions in smoking),
and age adjusted cancer death rates by population since have been declining for many types of cancer,
this disease is still a major killer of Americans (Cancer Facts & Figures 2021-PDF download).
If we want dramatic reductions in cancer death rates, we need to use much more of our brainpower and talent to focus on the big picture and not just individual cancer studies.
We need a strategic plan that assesses what we know and what we need to know. This is a risky enterprise. Much of this strategic plan is “informed guesswork” that will fail, at least in part. But success comes from persistence and from learning from our mistakes. We have cured childhood leukemia, Hodgkin lymphoma, testicular cancer and other childhood tumors (Siegel 2021), but this occurred not with a “silver bullet” or a magical drug, but through rigorous scientific investigation and extensive use of clinical trials to make slow progress over the years (Emperor Of All Maladies, 2011).
Sadly, no national institution has developed a strategic plan to cure cancer. The National Cancer Institute does strategic planning, but to my knowledge has no plan with curative targets. Neither does the American Cancer Society, the American Medical Association or any other institution or organization.
Let’s cure cancer together.
We have developed a plan. It needs a lot of work, but is a start (see Strategic Plan to Cure Cancer). We will update it regularly.
How can you help?
* Join our Curing Cancer Network, which has monthly E-blasts about our efforts and related efforts by others; click here.
* Read our American Code Against Cancer and pledge to do all you can to prevent becoming a cancer statistic.
* If you are a scientist or physician, review our plan and give me your feedback at Nat@PathologyOutlines.com.
* For other ways to help, click here.
Let’s get to work.
Curing Cancer blog – part 9 – How cancer kills
Revised 11Apr21
This blog discusses curing cancer based on the principles of complexity theory. Follow this blog at https://natpernickshealthblog.wordpress.com and join our Curing Cancer Network to receive weekly status updates by clicking here (note: this project is independent of PathologyOutlines.com).
Our strategic plan is to reduce US cancer deaths from 600,000 in 2021 to 100,000 by 2030. To do so, we must better understand how cancer actually kills people. We conclude that cancer often kills by promoting marked physiologic disruptions in life’s essential networks and by creating a sense of futility, which causes individuals and the medical system to give up the fight. Other direct mechanisms include hemorrhage, infection, side effects of therapy, central nervous system changes and organ failure.
1. Life requires a sophisticated web of stable biologic networks
To understand death, we must understand life’s requirements. To live, we require adequately functioning organs and organ systems within a supportive and stable biologic environment that these organ systems themselves help create and maintain through a sophisticated web of network interactions.
Life follows the principles of complex systems in that the properties of the entire system are greater than the sum of the properties of each part due to interactions between the parts (Pernick 2017). This synergy gives us a greater capability than we might imagine from studying each organ system separately but also creates difficult problems when multiple interdependent systems go awry.
Our cells function optimally only when supplied by blood with adequate oxygen and glucose and when the concentration of essential blood components is maintained within a narrow range. These include sodium and potassium (electrolytes), calcium and other minerals, acidity (pH) and nutrients. In addition, the immune system must limit destructive infections and their toxins, the coagulation system must preserve blood flow and prevent hemorrhage and the kidney and liver must detoxify harmful substances and remove them from the body.
2. Cancer kills by promoting marked physiologic disruptions
We propose that cancer kills by promoting marked disruptions in life’s essential biologic networks. Our organ systems have evolved to be tightly integrated with each other for optimal performance, to respond to the usual physiologic conditions and to correct small, short term disturbances. This explains why humans typically have a prolonged lifespan that only occasionally requires significant medical intervention. Cancer risk factors cause sustained stress on the networks, leading to initially small, unnoticeable changes. However, self-organized criticality predicts that over long time periods, these small changes, acting in a nonlinear manner, may lead to an avalanche of changes (Bak, How Nature Works 1999), which may cause marked physiologic disturbances and unstable states involving tumor growth and spread, the release of cytokines, inflammation, immune system dysfunction and other changes to the metabolic milieu. These “cancer attractor” states are difficult to normalize, even with intensive medical therapy and ultimately may lead to a downward spiral causing death.
Cancer risk factors and the malignant process create disruptions by several mechanisms: (a) they promote continuous activation of the inflammatory system, which is unstable and transmits this instability to the many networks with which it interacts (Pernick 2020); (b) tumor growth destroys normal tissue, which diminishes the effectiveness of organ systems and their cooperation with other organ systems or even causes organ failure; (c) growing tumors cause increased metabolic demands, which challenge network functioning; (d) tumors secrete products which disturb physiologic functions; (e) tumor growth may, over time, induce network changes that trigger cellular activities typically repressed in adults, such as unicellular programming for cells and embryonic differentiation; (f) tumor growth may create immune system dysfunction that leads to tolerance of cells with malignant properties that would otherwise be destroyed. Together, these mechanisms may lead to a dominance of cancer attractor networks which preserve malignant properties in organ systems, even against treatment, and are ultimately incompatible with life.
Our organ systems are interdependent so that disturbances in one system may cripple many systems. For example, cancer causes disturbances in the blood calcium level that affects the kidney, gastrointestinal tract, central nervous system and skeletal system (Zagzag 2018). Cancer or its treatment may damage the bone marrow, leading to anemia, bleeding or infections, all of which similarly degrade the functioning of multiple organs and organ systems.
3. Countering cancer related disruptions is difficult
In general, human physiology or medical practitioners are capable of countering slow declines in the functional capacity of organs, particularly when there are deficiencies in only one organ system, due in part to organ system redundancy and reserve. However, cancer kills patients because (a) systems fail quickly, challenging our ability to respond promptly and appropriately; (b) it is difficult to adequately respond when multiple critical organ systems fail simultaneously because the usual treatments for single system failure may be inadequate; (c) even before the rapid decline, these organ systems were slowly diminishing due to tumor related destruction or age related changes.
When multiple organ systems are working harmoniously, we marvel at the wonders of life. However, dysfunction in multiple systems produces not just abnormal lab values that threaten life, as assessed by medical scoring of physiologic instability (Mattia 1998, Pollack 1996), but the inability to easily return these physiologic measures to normal.
It is important to note that cancer typically does not kill by destroying the functional capacity of organs to the extent that they no longer sustain life. When people die of cancer, particularly if this occurs rapidly after diagnosis, they usually have adequate reserves of function in their organs or these reserves can be supplemented by technology.
Rapid cancer deaths have similarities to diabetic ketoacidosis in that both are lethal primarily due to abrupt physiologic changes, not because the patient is terminally ill. In diabetic ketoacidosis, insulin deficiency transforms an orderly physiology into chaotic, life threatening disturbances in many essential networks. Merely giving insulin does not fix the problem – instead, a sophisticated system of treatment and monitoring is required (Fayfman 2017) that is so complicated that simulations are often used in training (Roberts 2020).
Similarly, we suggest that rapid cancer deaths could be reduced with a sophisticated system of treatment and monitoring. The initial concern should be countering the tumor’s disruptive effects on network related stability so that medical therapy can restore viable physiologic characteristics and maintain life. Subsequent treatments can focus on killing the bulk of the tumor cells and achieving long term survival.
4. A sense of futility is another major cause of cancer death
Another major mechanism of cancer death is futility, the belief that there is no reasonable hope for a cure or benefit to continued treatment. With advanced cancer, the physiologic changes are persistent, but not necessarily rapid; although medical science can halt them temporarily, patients and their physicians may believe it is futile to aggressively manage what is clearly a downhill process.
Even with progression, life can continue as long as there are no rapid instabilities and if patients and their physicians rationally believe there is hope to continue. If cancer is viewed as a chronic disease that can be managed (even if not cured) and as newer treatments improve our ability to hold it in check, then we can limit this sense of futility and diminish cancer related deaths, at least for some time. Anti-tumor treatment may incorporate the principles of adaptive therapy, which uses more dynamic treatment protocols, such as (a) suppressing the growth of resistant phenotypes, (b) creating an initially small resistant tumor cell population that is eradicated by a second treatment, (c) designing a “resistance management plan” and (d) at some point, assessing the success of treatment in each patient and determining what could be improved for future patients (Stanková 2019).
6. Occasionally, cancer does kill directly
Cancer can kill directly by eroding blood vessel walls, leading to lethal hemorrhages, which either damages vital brain functions or causes loss of blood flow throughout the body, starving cells of oxygen and nutrients. In addition, brain tumors can cause increased intracranial pressure, leading to brainstem herniation, which blocks the nerve signals to the lungs for breathing. Cancer treatment or its persistence can damage immune system and bone marrow function, leading to life threatening infections, anemia or coagulation disturbances, which also cause death.
In summary, we propose that to prevent cancer related deaths, cancer treatment must also focus on countering the physiologic disruptions it creates. In addition, cancer should be viewed as a chronic disease that although sometimes curative, often will not disappear but can be managed for long periods of time.
Thanks to Philip Agop Philip, MD, PhD, FRCP, Professor of Oncology and Pharmacology, Karmanos Cancer Institute / Wayne State University, for his careful and constructive review (FRCP: Fellow, Royal College of Physicians).
Curing Cancer – How you can help
Last revised 16 June 2021
Our strategic plan is to reduce US cancer deaths from the current 600,000 per year to 100,000 per year by 2030. It has been 50 years since the war on cancer was announced by President Nixon – it’s time we start to implement an overall strategy, imperfect as it may be, and improve it over time. Of course, some national organization should be leading this effort, but they are not. So let’s do the best we can on our own and save as many lives as we can.
How can you help?
- Follow our Curing Cancer Blog at https://natpernickshealthblog.wordpress.com/ .
- Sign up for our Curing Cancer Network monthly newsletter by clicking at https://lp.constantcontactpages.com/su/onz6IND . You can also Text CURINGCANCERNET (with no spaces) to 22828 to sign up.
- Become an example to others of anti-cancer behavior. Read our American Code against Cancer at http://www.natpernick.com/AmericanCodeAgainstCancer.html, decide what steps you can take to reduce your cancer risk and spread the word through your social networks.
- Tell any medical researchers you know about our current grants at https://www.pathologyoutlines.com/grants.html.
- Contact me at Nat@PathologyOutlines.com with your suggestions or thoughts on how you can help.
Curing Cancer – The American Code Against Cancer
15 April 2021
Click here for the most recent version.
The American Code Against Cancer focuses on actions that individuals can take to help prevent cancer. Successful cancer prevention also requires supportive governmental policies and actions. Following these recommendations reduces cancer risk by 30-40% and should produce substantial progress towards our strategic plan goal of reducing US cancer deaths from 600,000 projected in 2021 to 100,000 deaths annually by 2030.
- Do not smoke or use any form of tobacco.
- Make your home smoke free.
- Try to achieve a healthy body weight with a BMI of 25 or less.
- Be physically active.
- Have a healthy diet based on vegetables, fruits and whole grains. Limit sugar, fat, processed meat and red meat.
- If you drink alcohol, limit your intake. Not drinking alcohol reduces your cancer risk.
- Avoid too much sun, especially for children. Use sun protection. Do not use tanning beds.
- Protect yourself against cancer causing substances in the workplace by following health and safety instructions.
- Check that your residence does not have high radon levels.
- For adults:
- Get a physical exam every 1-2 years to detect possible problems, discuss risk prevention and get needed tests, screenings and vaccinations.
- Get a one time screening for Hepatitis C if you were born between 1945 and 1965.
- Get an annual lung screening if you are a current or former heavy smoker age 50-80.
- For adult women:
- Breastfeed your baby, if you can, to reduce your cancer risk.
- Limit use of hormone replacement therapy.
- Get screened for colon cancer, breast cancer and cervical cancer.
- For adult men:
- Get screened for colon cancer.
- For children:
- Get vaccinated for Hepatitis B and HPV to reduce cancer risk.
The American Code Against Cancer is based on the European Code Against Cancer with modifications from the Centers for Disease Control-Lung Cancer Screening and the American Cancer Society-Liver Cancer.
Send comments to Nat@PathologyOutlines.com.
How pancreatic cancer arises, based on complexity theory
26 February 2021
This is the third paper in a series discussing the top 20 causes of US cancer death and how they arise based on complexity theory (see How Lung Cancer Arises-Pernick 2021 (PDF), How Colon Cancer Arises- Pernick 2020 (PDF)). We first discuss the population attributable fraction of pancreatic cancer risk factors and their mechanism of action, then integrate these mechanisms into our theory about how cancer arises in general and in the pancreas, and finally suggest curative treatment approaches for pancreatic cancer.
Highlights:
- Countering pancreatic cancer requires optimizing all factors affecting it, even if not directly part of the malignant process.
- Five “super promoter” mechanisms cause pancreatic cancer: random chronic stress (bad luck or cellular accidents); chronic inflammation; DNA alterations; immune system dysfunction (individual and “societal”) and hormones (insulin-IGF system).
- The 5 major causes / risk factors of pancreatic cancer are random chronic stress (causes 25-35% of cases); non O blood group (17% of cases); excess weight, particularly at younger ages (15%); cigarette smoking (15%) and type 2 diabetes (9%).
- Cancer arises in part because risk factors activate embryologic and inflammatory pathways in a manner that cannot be turned off.
- In the pancreas, tumor cell spread may occur even before a primary malignancy arises, explaining why advanced disease is often found at diagnosis.
- Treatment approaches should focus on network dysfunction not mutations; combinations of combinations of treatment to block multiple webs of network abnormalities; treating and monitoring key systemic network changes outside the primary tumor; enrolling all patients in clinical trials and creating stronger public health programs to prevent these cancers or detect them earlier.
Curing Cancer – Part 8 – Strategic plan for curing cancer (as of February 2021)
16 February 2021
This series is about curing cancer based on the principles of complexity theory. Follow my blog at https://natpernickshealthblog.wordpress.com.
This is the initial version of my strategic plan. The current version is here.
It has now been 50 years since the war on cancer was announced by President Richard M. Nixon (see President Nixon’s 1971 State of the Union at 15:03).
Although age adjusted cancer death rates have dropped substantially from 1970 to date (men: 249.3 to 189.5 per 100,000; women: 163.0 to 135.7 per 100,000), the American Cancer Society still projects that 608,570 Americans will die of cancer this year (Jemal 2010; US National Cancer Institute website, Cancer Facts & Figures 2021).
This essay provides a strategic plan for curing cancer. Regular updates are anticipated as our understanding of cancer related networks increases and progress is made in the steps below.
How to define victory in the war on cancer?
I define “curing cancer” as reducing American cancer deaths to 100,000 per year. Further major reductions are unlikely, because some patients will be ineligible for curative treatment due to coexisting medical conditions, some patients will refuse treatment and all of us will eventually die of something.
What changes are needed to reduce cancer deaths to this level?
The first step in curative therapy is halting cancer cell growth, which involves several distinct approaches.
1. Institute more effective treatment for the primary tumor.
1a. Develop more effective treatments to kill the cancer cells that damage critical tissues and organs. Some patients need immediate treatment because their cancer is life threatening due to its advanced and aggressive nature. This includes childhood leukemia patients and some adult patients, such as actor Dustin Diamond, who died of disseminated small cell lung cancer shortly after diagnosis. We should shift our focus from targeting driver mutations (i.e. specific mutations common in a particular tumor) towards targeting dysfunctional cellular networks which include the driver mutations. This is admittedly more difficult, due to possible alterations in many genes in the network plus all of the components with which the genes and their products interact (Barabási 2011).
1b. Curative treatment must attack different aspects of the cancer, requiring combinations of combinations of treatment. Disabling any single cancer attribute, such as rapid cell growth, will likely require combinations of 3-5 drugs or other treatments (radiation therapy, hyperthermia) because each attribute develops through activation of a web of biologic pathways that readily bypasses a single treatment block (Curing Cancer Blog-Part 4).
Interactions of cell cycle pathways resemble a web (Wikipedia)
Disabling each additional cancer attribute, such as cell migration (metastatic spread), avoiding programmed cell death (apoptosis) and the systemic networks described below, may require a different combination of treatments, although there may be some overlap. This means that patients must typically receive combinations of combinations of treatments.
1c. Treatments must be extensively tested in clinical trials to optimize their delivery, make them tolerable to patients and ensure that they work well together. Towards this end, every cancer patient should be enrolled in a clinical trial. In addition, computational approaches and modeling methods may be useful to determine the effectiveness of treatment combinations (Curing Cancer Blog-Part 5).
1d. It may be important to “normalize” or reduce the malignant traits of tumor cells that survive the above steps. This involves treatments that push tumor cell networks out of their relatively stable “attractor” states towards network states with reduced malignant properties (Curing Cancer Blog-Part 5).
2. Attack and monitor systemic networks that promote malignancy.
Many systemic network changes promote and maintain the primary cancer and produce new malignancies (Curing Cancer Blog-Part 6). Curative therapy requires that we attempt to “normalize” or at least block the most harmful aspects of these network changes and that we monitor their status as treatment is given. This monitoring should supplement existing radiologic and clinical studies that determine the size and extent of the known tumor. For each network, we must determine what biological molecules to monitor, how best to do so and how changes in their values should affect treatment. It may be useful to develop a cancer network score analogous to the TNM staging score for tumors that predicts prognosis and suggests future treatments.
These changes to systemic networks appear to be most important:
2a. Attack the inflammatory process, which has a central role in promoting and sustaining carcinogenesis. Physiologic inflammation activates quiescent networks to initiate sophisticated repair, antimicrobial and antitumor processes and then shuts down, because this activation also triggers pathways promoting its resolution (Serhan 2005). However, cancer risk factors trigger inflammation through nonconventional means that do not initiate the resolution process (Fishbein 2020). This causes chronic (persistent) inflammation, which may wear down stabilizing factors in inflammatory and adjacent networks, particularly when accompanied by other risk factors, which further drives the malignant process (Shimizu 2012, Morgillo 2018, Huang 2009).
The link between inflammation and carcinogenesis
Chronic inflammation must be treated directly – it has previously been proposed to be one of 5 “super promoters” of cancer (Curing Cancer Blog-Part 7).
Possible treatment options for chronic inflammation include: (a) triggering pro-resolution pathways (Fishbein 2020, Park 2020); (b) administering anti-inflammatory agents (Zappavigna 2020); (c) using agents that mimic physiologic halting mechanisms associated with wound healing (Shah 2018) and liver regeneration (Abu Rmilah 2019); and (d) countering germline (inherited genetic) changes that promote additional instability in the inflammatory process.
2b. Disrupt the microenvironment that nurtures tumor cells at primary and metastatic sites. Chronic inflammation and cancer risk factors produce a microenvironment that nurtures mutated cells, steers cellular networks towards malignant pathways (Mbeunkui 2009), helps them escape immune system surveillance (Labani-Motlagh 2020) and activates cancer cells to mimic physiologic “invasion” of wounded epithelium through the extracellular matrix (which provides structural support for cells and a proper microenvironment for optimal function) (Bleaken 2016). Tumors require a fertile “soil” for the cancer “seeds” to grow (Fidler 2003) and co-opt physiologic control mechanisms (Coussens 2002). In the correct microenvironment, tumor cells themselves may produce cytokines (small biologically active proteins) that promote their own survival (Wang 2019, Das 2020).
Targeting aspects of the inflammatory microenvironment that are active in particular tumors and that provide supportive blood vessels (Gkretsi 2015), stroma and extracellular matrix (Mpekris 2020) is important. Targeting the microenvironment may also enhance drug delivery and effectiveness (Polydorou 2017) and make existing tumors or premalignant states more susceptible to immune system attack (Mpekris 2020). It is also important to disrupt the microenvironment of possible metastatic sites. Typically, tumor cells die at secondary sites but the malignant process preconditions this otherwise hostile microenvironment to make it conducive to the growth of disseminated cancer cells (Houg 2018, Kaplan 2005, Li 2020).
2c. Disrupt the microenvironment that promotes embryonic features associated with aggressive tumor behavior. Embryonic cells resemble cancer cells due to their rapid proliferation, tissue invasion and long distance migration (López-Lázaro 2018). In the microenvironment of the fertilized egg, coordinated network activity ultimately moves embryonic related networks towards mature, differentiated phenotypes in the newborn. Cancer risk factors also activate these networks to similarly trigger rapid cell division (Kermi 2017), cell migration (Reig 2014, Kurosaka 2008) and changes to cell differentiation (Li 2014) but in a destructive manner. Since these risk factors act in a noncoordinated manner, these networks persist in an activated state and do not mature over time. Curative treatment should include agents that promote this maturation, such as retinoids used in acute promyelocytic leukemia (Madan 2020), myeloid differentiation promoting cytokines (McClellan 2015), other cancer cell reprogramming drugs (Gao 2019, Gong 2019) or possibly agents that halt rapid cell division in embryogenesis (Kermi 2017).
2d. Correct immune system dysfunction that coevolves with carcinogenesis. The immune system consists of a sophisticated web of interacting networks, including the innate immune system (nonspecific defense mechanisms, including macrophages, neutrophils, dendritic cells, natural killer cells, mast cells, eosinophils and basophils), the adaptive immune system (antigen specific immune response involving lymphocytes and antibodies), extracellular matrix, stromal fibroblasts and regulatory molecules. Since malignant progression systemically degrades the performance of many of these components (Karamitopoulou 2020), combinatorial therapy is needed to target multiple aspects of immune dysfunction (Sodergren 2020) instead of focusing on just one pathway (Li 2019).
2e. Activate gene networks supporting stable, multicellular processes and suppress networks supporting malignant-like unicellular processes. Multicellular organisms evolved from unicellular organisms by adding new genes and more intricate controls to existing networks supporting cell metabolism and replication (Trigos 2018, Trigos 2019). This enabled greater communication and coordination between cells and made possible higher level functions, such as cell differentiation and programmed cell death (Trigos 2018). The new multicellular control mechanisms keep cellular and systemic processes on track and shift the survival focus away from individual cells towards the organism as a whole (Davies 2011). Inflammation and DNA alterations damage multicellular controls, activating an existing genetic toolkit of preprogrammed, malignant behavior in unicellular networks based on what has been described as the atavism hypothesis of cancer (Davies 2011, Trigos 2017, Bussey 2017).
Curative treatment should activate multicellular networks and suppress unicellular networks (Gaponova 2020, Hay 1995). Innovative treatments could also target cancer cell weaknesses by applying a specific cellular stress that is readily dealt with by healthy cells using multicellular programming but not by cancer cells with predominantly unicellular programming (Lineweaver 2014). This includes “lethal challenges” of high dose methotrexate with leucovorin rescue (Howard 2016) or targeting other aspects of chaotic or unstable states, such as cell-extracellular matrix detachment (Crawford 2017).
2f. Antagonize hormones that may promote tumor growth. Physiologic (i.e. normal) levels of estrogens and androgens and elevated levels of insulin are associated with cancers of the breast (Dall 2017), endometrium / uterus (Rodriguez 2019), prostate (Liu 2020) and pancreas (Li 2019, Perry 2020). The primary mechanism may involve promotion of cell growth, particularly during stages in life when these cells are particularly vulnerable to instability.
Simple antagonism of hormonal pathways is possible using tamoxifen for estrogens, antiandrogens for testosterone and metformin for insulin (Wan 2018). One block in these pathways may be adequate for normalization, in contrast to the 3-5 blocks required for other tumor cell networks. Behavioral changes such as weight loss, exercise, a healthier diet and reducing alcohol and tobacco use may also be therapeutic by either altering hormone levels or changing their interaction with other risk factors.
2g. Target germline changes that promote malignant behavior. Genetic testing of nontumor cells (germline testing) is recommended for all patients with pancreatic cancer (Stoffel 2019) and select patients with other cancers or family histories of cancer (Daly 2020, Lincoln 2020). Results are currently used to determine antitumor therapy (Zhu 2020) as well as for cancer screenings, reproductive choices and genetic counseling. These results should also be used to provide treatment that: (a) moves premalignant or malignant cells into less harmful pathways, as discussed above or (b) counters common germline changes that promote malignancy in inflammatory, DNA repair, cell cycle stability, immune system or other networks.
3. Strengthen public health and preventative programs. A curative treatment strategy includes establishing strong public health programs that promote cancer risk reduction, establish effective screening programs and ensure that all patients get adequate medical care.
3a. Public health programs should reduce personal behavior that promotes malignancy. Public health agencies should create professionally crafted messages that promote a culture of being healthy so that everyone is encouraged to make their own health a priority. This includes encouraging behavioral changes, such as reducing smoking, excess weight and alcohol abuse and encouraging a healthy diet, exercise and vaccinations (European Code Against Cancer, accessed 16Feb21). At a societal level, our public health and medical care systems act as a behavioral immune system (Schaller 2015) to reduce cancer risk factors. Our physiologic immune system prevents numerous cancers from being clinically evident, as demonstrated by the high cancer rate in immunosuppressed patients due to drugs, diseases (HIV) or genetic disorders. Similarly, a well run public health system that promotes risk factor reduction will prevent many cancers from arising.
3b. More effective screening programs are needed to identify premalignant or malignant lesions in both high risk patients and current cancer patients being monitored for relapse. Testing for the presence of chronic inflammation may also be useful, but we must determine what specifically to test for.
3c. Government policy should ensure that all patients have easy access to optimal medical care. At an individual level, optimal medical care promotes the reduction of behavioral risk factors, earlier detection of disease and increased use of effective treatments not available to those with inadequate care, poor performance status or severe comorbidities (Kelly 2016). Promoting overall societal health also changes the nature of malignancies that remain and makes it easier to focus on their effective treatment.
4. The next steps to promote this strategic plan include:
(a) Public dissemination of this strategic plan with requests for feedback and collaboration from:
* Medical institutions (medical schools and medical centers, physicians, scientists and researchers)
* Health advocacy organizations (American Cancer Society, American Lung Association, American Medical Association, AARP)
* Elected officials and public health agencies at the city, county, state and federal levels.
(b) Continued analysis of the leading causes of cancer death to determine additional treatment principles or network targets;
(c) Direct funding of research programs to test the principles outlined above.
Please email NatPernick@gmail.com to collaborate or for further information.
New grant offering – 15Feb21
I am accepting applications for a single, nonrenewable grant of up to $10,000 for a research study of possible intermediate states for glioblastoma detectable by molecular methods. Click here (PDF download) for details.
Curing Cancer – Dustin Diamond dies of lung cancer
10 February 2021
TV actor Dustin Diamond, age 44, died of widely disseminated (stage 4) small cell lung cancer only one month after diagnosis (NBC News). This essay discusses, in a relatively nontechnical manner, important aspects of this disease and prospects for future curative treatment (MedPage Today).
What is cancer?
Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. It is classified based on the origin of the cells that becomes malignant: carcinoma (from cells that line or cover internal organs or are in the skin), sarcoma (from bone or soft tissue / connective tissue), lymphoma (from lymphocytes, a type of white blood cell) and some less common types.
What is small cell lung cancer?
Lung cancer is the leading cause of US cancer death and is predicted to cause 21.7% of the 608,570 projected US cancer deaths in 2021 (Cancer Facts & Figures 2021). Lung cancer is subclassified into nonsmall cell carcinoma (primarily squamous cell carcinoma and adenocarcinoma) and small cell carcinoma. These categories have distinct differences in behavior and treatment.
Small cell carcinoma of the lung arises from rare neuroendocrine cells in the respiratory tract which receive input from nerves and produce hormones. As in Dustin’s case, it is typically aggressive, with a poor prognosis and no curative treatment (PathologyOutlines.com-Small cell carcinoma). Microscopically, the tumor is composed of relatively small (compared to other cells) blue cells, which are mostly nuclei with little cytoplasm. The cells are fragile and often appear smudged on biopsy.
What causes lung cancer?
Over 80% of lung cancer cases are caused by cigarette smoking, which exposes cells throughout the respiratory tract to its 7,000 chemicals, including 60+ carcinogens. Other common causes are secondhand smoke, radon exposure and occupational exposure to hazardous substances. The table below indicates what percentage of lung cancer in the US is caused by various risk factors (note: since risk factors overlap, the totals add up to more than 100%):
There is also a baseline rate of lung cancer, estimated at 2 cases per 100,000 population per year in the US, which occurs without any risk factors, which I attribute to “random chronic stress” or cellular accidents (Curing Cancer Blog-Part 7).
On the cellular level, life is considered to follow the principles of self-organized criticality. This means that our cells, tissues and organs are relatively stable but a small change can rarely set off an avalanche of other changes leading to a catastrophic condition. For lung cancer, the carcinogens in cigarette smoke alter the DNA of cells in the lung and also induce a chronic inflammatory reaction that, over time, produces an environment that makes the catastrophe of malignancy more likely to arise. Typically, it takes decades between the initial changes and a clinically obvious tumor.
How does cancer kill people?
Human life requires functioning, interdependent organs. Malignant tumors (tumor just means a growth) destroy cells so these organs cannot function. For example, this tumor (an adenocarcinoma) has destroyed much of the lung:
Over time, cancer spreads to neighboring tissue and may enter blood vessels or lymphatic vessels to disseminate throughout the body with similar destructive effects.
Aggressive cancers, including most lung and pancreatic cancers, appear to have “hijacked” cellular programs used during embryogenesis, when rapid cell division and migration of cells serve a useful purpose. As the embryo matures, this programming is turned off. However, the presence of chronic inflammation, carcinogen exposure, hormones (for some cancers), immune system dysfunction and cellular accidents, over years to decades, may create an environment that reactivates this programming. Unfortunately, the adult cellular environment, unlike that in the embryo, has no mechanism to turn it off (Curing Cancer Blog-Part 6).
Cancer also arises due to activation of an evolutionarily ancient “toolkit” that was active in the single cell precursors of human beings but is typically suppressed by additional controls that evolved in multicellular organisms. This is called the atavism theory of cancer (Davies 2011).
How to cure these aggressive cancers?
Dustin’s rapid death resembles that of children with childhood leukemia before the 1950s, when most died within weeks to months of diagnosis (The Emperor of All Maladies). Curative treatment today for childhood leukemia is based on a combination of drugs which individually kill a large proportion of tumor cells or facilitate the action of other drugs to do so. Extensive clinical trials have determined that there are actually dozens of different leukemic diseases, each with different optimal treatments (see Table of Contents of PathologyOutlines.com-Bone marrow neoplastic chapter).
For aggressive adult tumors, we need to develop more effective single treatments and combinations of treatments to kill tumor cells or make them less destructive (Curing Cancer Blog-Part 5) . We also need to treat and monitor systemic changes that nurture the tumor (Curing Cancer Blog-Part 6). Enlisting as many patients as possible in clinical trials will facilitate these efforts. Long term, we need to reduce or counter patient risk factors that continue to produce new tumors.
Prevention is also treatment. Strong public health programs are needed to give professionally crafted messages about smoking, excess weight, radon, healthy eating, exercise and vaccinations (European Code Against Cancer). It is important to create a culture of being healthy so that everyone is encouraged to make their own health a priority. We also need to develop better screening tests for aggressive cancers, analogous to high blood pressure or cholesterol for heart disease and strokes. Testing for chronic inflammation may be useful, but we must determine what specifically to test for.
Together, these strategies will reduce the shock and devastation of cancer death that are all too common today.
Curing Cancer – Part 7 – Random chronic stress / bad luck as a major cause of cancer
31 January 2021, revised 16 June 2021
This is my seventh essay about curing cancer based on the principles of complexity theory. This essay discusses random chronic stress / bad luck, a major cause of pancreatic cancer (Pernick 2021) and lung cancer in nonsmokers (Pernick 2018).
Key concepts discussed are: (1) random chronic stress / bad luck is a major cause of cancer at some sites; (2) cancer often develops through rare bursts of activity in cells and their networks, not in a gradual, step-wide manner; (3) cancers due to random chronic stress may have better survival and other clinical differences compared with cancers due to traditional risk factors; and (4) due to the presence of random chronic stress, cancer will always be with us, although we can prevent some cases, we can detect it earlier and we can treat it more effectively.
What is random chronic stress / bad luck?
Random chronic stress / bad luck refers to rare, seemingly random cellular “accidents” that cause network dysfunction that may propagate to surrounding cellular networks and promote malignancy. These accidents are due to: (a) DNA replication errors in noncancerous stem cells (Tomasetti 2015, Tomasetti 2017), estimated at 1 per 100,000 nucleotides but reduced to 1 per 100 million nucleotides after error correction occurs (Pray 2008); (b) errors in how DNA is organized or modified by epigenetic events (Wikipedia-Cancer epigenetics, accessed 26Jan21); (c) errors in the distribution of cell components during cell division, such as transcription factors (López-Lázaro 2018a); (d) failure to restore physical interactions between tissue components after cell division, such as contact inhibition (López-Lázaro 2018b); (e) immune system dysfunction that, for a particular patient, is ineffective at eliminating premalignant or malignant cells. In addition, cancer risk factors not yet discovered, too infrequent to achieve statistical significance or not clinically evident in a patient, such as chronic pancreatitis without symptoms (Fujii 2019) or microscopic changes (Cobo 2018) may be erroneously included in the category of random chronic stress / bad luck.
How does a random event lead to cancer?
Self-organized criticality, which describes catastrophic events such as earthquakes and stock market crashes, helps us understand how a single random event in a cell can propagate to malignancy. Our cellular networks are poised at a critical state in which small disturbances typically cause no network changes, occasionally cause small network changes and rarely set off a cascade of changes in the initial network and those it interacts with (Bak, How Nature Works 1999). By analogy, individual grains of sand dropped on a sandpile usually have no apparent impact, occasionally cause small avalanches and rarely cause the entire sandpile to collapse. Dropping a single grain of sand with no apparent impact causes small structural changes in the sandpile that ultimately may enable an additional grain to set off an avalanche. It is important to focus on the sandpile itself as the functional unit, not the grain of sand (Bak, How Nature Works 1999). Similarly, cellular networks are the functional unit when studying malignancy, not the individual mutations.
Self-organized criticality is nature’s way of making enormous transformations over a short time scale based on individual factors often thought too trivial to consider. In punctuated equilibrium of species, one sees prolonged periods of apparent stasis (i.e. no new species), followed by bursts of new species (Eldredge & Gould 1972). During the “quiet” periods, minor changes are accumulating. Similarly, human cellular networks have long periods with accumulation of minor changes with no apparent clinical or microscopic changes, followed by bursts of activity leading to obvious premalignant or malignant changes (Cross 2016). Self-organized criticality contrasts with the theory of gradualism, in which major changes occur due to the steady accumulation of small changes that produce visible differences. Gradualism is logical and predictable and was promoted by Darwin (Gould 1983) but it does not accurately describe evolution or malignant progression (Sun 2018).
How does cancer due to chronic random stress differ from other cancers?
Cancer due to random chronic stress differs from cancers caused by traditional risk factors, such as cigarette smoking, in two important ways. First, the rate of cancer due to random chronic stress is much lower. We previously estimated the rate of lung cancer due to random chronic stress at 2 cases per 100,000 men and women per year, compared with the current age adjusted US incidence of lung cancer, due primarily to cigarette smoking, of 54 cases per 100,000 (Pernick 2018). However, random chronic stress may account for 50-70% of lung cancer cases in nonsmokers in North America and Europe (Pernick 2018). For pancreatic cancer, random chronic stress is also estimated to cause 2 cases per 100,000 people per year (age standardized) compared with the current age standardized rate of 7.7 in Europe and 7.6 in North America (Pernick 2021; Rawla 2019); it may be the most common risk factor for pancreatic cancer, accounting for 25-35% of US cases (Pernick 2021).
Second, clinical characteristics of resulting cancers may be different. For lung cancer, there are striking differences between the epidemiological, clinical and molecular characteristics of lung cancer in cigarette smokers (80-90% of cases) compared with never smokers that have led some authors to conclude that they are distinct clinical entities (Yano 2008, Smolle 2019). Never smokers with lung cancer have a higher predominance of women, more frequent Asian/Pacific Islander or Hispanic ethnicity, a higher frequency of adenocarcinoma histology, more frequent EGFR mutations and ALK rearrangements and superior survival when adjusted for standard prognostic factors (Pernick 2018). Never smokers with lung cancer may have a higher predominance of women and Asians because these groups make up a larger percentage of never smokers (Tsai 2008).
For pancreatic cancer, cigarette smoking is also associated with higher death rates and poorer survival (Ben 2019, Yuan 2017). However, unlike lung cancer, pancreatic cancer has other risk factors causing a high percentage of cases, namely non O blood group, excess weight and type 2 diabetes, as well as less prominent risk factors of excessive alcohol use, diet, family history / genetic and chronic pancreatitis (Pernick 2021). To date, we are not aware of any studies comparing clinical and molecular characteristics of pancreatic cancer patients with and without these risk factors.
There are two reasons that patients with lung or pancreatic cancer due to random chronic stress may have superior survival. First, these tumors may be less aggressive due to fewer molecular alterations that disrupt networks. For example, cigarette smokers have decades of exposure to 7,000 substances in tobacco smoke, including at least 60 carcinogens (The Health Consequences of Smoking – 50 Years of Progress: A Report of the Surgeon General 2014, page 154, PDF page 183), which causes a heavy burden of network alterations and DNA change affecting multiple biologic pathways. Analysis of a case of poorly differentiated lung adenocarcinoma showed more than 50,000 single nucleotide variants (Lee 2010), and a small cell lung cancer cell line had over 20,000 somatic mutations (Pleasance 2010). This level of mutations likely overwhelms the capacity of the DNA repair pathway, both due to its magnitude and because mutations may damage the repair pathways themselves and may be associated with particularly aggressive disease.
Second, changes due to random chronic stress most likely occur in only one cell. In contrast, cancer risk factors, such as cigarette smoking, have a field effect, promoting network changes that may promote malignancy in a broad range of cells exposed to the risk factor (Steiling 2008, Lochhead 2015).
Why cancer will always be part of our world
The American Cancer Society does great things, but its mission statement, “The American Cancer Society’s mission is to save lives, celebrate lives, and lead the fight for a world without cancer” (accessed 31Jan21) is irrational. Even if we could totally eliminate all cancer risk factors, the presence of random chronic stress / bad luck would ensure a steady rate of new cancer cases. A realistic strategy is not to eliminate cancer but to try to prevent cases by reducing risk factors, detecting cases earlier and developing more successful treatment.
Curing Cancer – Part 6 – Key systemic network issues
24 January 2021, revised 19 June 2022, click here.
This is my sixth essay about curing cancer based on the principles of complexity theory. This essay proposes strategies for curative therapy regarding key systemic networks other than those affecting the primary tumor, which were discussed in Curing Cancer – Part 5.
1. Disrupt the inflammatory process that plays a central role in promoting and sustaining carcinogenesis. Tumors have been described as wounds that do not heal (Dvorak 1986, Dvorak 2015). Activation of the inflammatory system, which promotes wound healing and accompanies many malignancies (Coussens 2002, Pernick 2020), has been considered a major cause of cancer since 1863, when Virchow speculated that some irritants enhance cell proliferation through tissue injury and chronic inflammation (Schottenfeld 2006). Inflammation is activated by many cancer risk factors, including excess weight, cigarette smoking, heavy alcohol consumption, aging and a Western diet (high fat, highly processed foods, low consumption of vegetables, fruits and whole grains) (Antwi 2016, Pernick 2020).
Inflammation may play a central role in promoting carcinogenesis because it is widely connected to other networks and it is unstable because it rapidly initiates sophisticated repair, antimicrobial and antitumor processes. Ultimately, this network instability may propagate to local and systemic networks and promote malignancy (Morgillo 2018).
Cancer disrupts the usual coordination of inflammatory networks. Sophisticated biologic processes, such as inflammation and embryogenesis, require coordination of activity, since isolated network activity by itself can be either useful or destructive, depending on its context. For inflammation, this coordination includes triggering both the process and its resolution at the same time (Serhan 2005, Serhan 2020). As the trauma is repaired or the threat from foreign organisms subsides, the resolution pathways cause networks to revert towards their initial states to prevent bystander damage to tissue (Sugimoto 2016). Cancer risk factors may also trigger the inflammatory process but through nonconventional means that do not simultaneously initiate the resolution process (Fishbein 2020). This causes persistent inflammation, which may wear down stabilizing factors in inflammatory and adjacent networks, particularly when accompanied by other risk factors, which further drives the malignant process (Shimizu 2012, Huang 2009).
Curative cancer therapy needs to antagonize or diminish this persistent inflammatory process. Suggested options include: (a) triggering pro-resolution pathways (Fishbein 2020, Park 2020); (b) using anti-inflammatory agents to diminish inflammation in general (Zappavigna 2020, Bruserud 2020); (c) mimicking the halting mechanisms associated with wound healing (Shah 2018, Kareva 2016) and liver regeneration (Abu Rmilah 2019); and (d) countering germline (inherited genetic) changes that promote instability in the inflammatory process.
2. Disrupt the microenvironment that nurtures tumor cells at primary and metastatic sites. Cancer risk factors produce a microenvironment that nurtures mutated cells, steers cellular networks towards malignant pathways (Mbeunkui 2009), helps them escape immune surveillance (Labani-Motlagh 2020) and ultimately promotes invasion by activating cells to mimic physiologic “invasion” of wounded epithelium through the extracellular matrix (Bleaken 2016, Coussens 2002). Tumors require a fertile “soil” for the cancer “seeds” to grow (Fidler 2003, Tsai 2014). For example, Hodgkin Reed-Sternberg cells produce cytokines that assist the survival and proliferation of lymphoma cells (Wang 2019) and pancreatic tumor cells produce cytokine IL1β and proinflammatory factors that establish a tumor supportive microenvironment (Das 2020, Huber 2020). From a network perspective, there is a complex crosstalk among cancer cells, host cells and the extracellular matrix (Sounni 2013).
Curative treatment should disrupt or normalize the microenvironment by targeting inflammation, the vasculature and the extracellular matrix (Mpekris 2020). For example, anti-VEGF or anti-VEGF receptor treatment can normalize vasculature by reducing vascular permeability (Gkretsi 2015). Normalizing the microenvironment may also enhance drug delivery and effectiveness (Polydorou 2017, Stylianopoulos 2018) or make existing tumors or premalignant states more susceptible to immune system attack (Ganss 2020).
It is also important to disrupt the microenvironment of possible metastatic sites. Typically, tumor cells die at secondary sites but the malignant process preconditions the otherwise hostile microenvironment of the secondary site so it can sustain their colonization (Houg 2018, Kaplan 2005).
3. Disrupt the microenvironment that promotes embryonic features associated with aggressive tumor behavior. In the microenvironment of the fertilized egg, coordinated network activity ultimately moves embryonic related networks towards mature, differentiated phenotypes in the fetus and newborn. However, cancer risk factors stimulate these networks in a non coordinated manner to trigger embryonic properties, such as rapid cell division (Kermi 2017), cell migration (Reig 2014, Kurosaka 2008) and changes to cell differentiation (Li 2014) that do not mature over time.
Curative treatment should include agents to promote this maturation, such as retinoids used in acute promyelocytic leukemia (Madan 2020), myeloid differentiation promoting cytokines (McClellan 2015), cancer cell reprogramming drugs (Gao 2019, Gong 2019) or possibly agents that halt rapid cell division in embryogenesis (Kermi 2017).
4. Repair the immune system dysfunction that coevolves with carcinogenesis. The immune system consists of a web of interacting networks whose effectiveness is systematically degraded with malignant progression. Immune dysfunction in cancer is typically not just the failure of one particular pathway (Karamitopoulou 2020). Curative treatment should attempt to improve immune system function with combinatorial therapy that targets multiple aspects of immune dysfunction (Sodergren 2020).
5. Promote the activation of gene networks supporting stable, multicellular processes and suppress networks promoting unicellular processes that support malignant type behavior. Multicellular organisms evolved from unicellular organisms by adding new genes and more intricate controls to existing networks for metabolism and replication (Trigos 2018, Trigos 2019). This enables greater communication and coordination between cells and makes possible higher level functions, such as cell differentiation and programmed cell death (Trigos 2018). The new control mechanisms keep cellular and systemic processes on track and shift the survival focus from individual cells towards the organism as a whole (Davies 2011). The operation of multicellular and unicellular programs appears to be somewhat mutually exclusive. Inflammation and DNA alterations may damage these multicellular controls, activating the existing genetic toolkit of preprogrammed, malignant behavior in unicellular networks based on what has been described as the atavism hypothesis of cancer (Davies 2011, Trigos 2017, Bussey 2017).
To restore the balance between multicellular and unicellular controls, curative treatment should activate different components of multicellular networks (Gaponova 2020, Hay 1995). In addition, treatment could target the weaknesses of cancer cells by applying a specific cellular stress that is readily dealt with by healthy cells using evolved capabilities or multicellular programming but not by cancer cells with predominantly unicellular programming (Lineweaver 2014). This includes “lethal challenges” of high dose methotrexate with leucovorin rescue (Howard 2016) or targeting other aspects of chaotic or unstable states, such as cell-extracellular matrix detachment (Crawford 2017).
6. Target the hormones that may promote tumor growth. Physiologic (i.e. normal) levels of estrogens and androgens and elevated levels of insulin are associated with breast (Dall 2017), endometrial / uterine (Rodriguez 2019), prostate (Liu 2020) and pancreatic cancer (Andersen 2017, Li 2019, Perry 2020). The primary mechanism may involve promotion of cell growth, particularly at a stage when these cells are particularly vulnerable to instability.
Simple antagonism of hormonal pathways is possible using tamoxifen for estrogens, antiandrogens for testosterone and metformin for insulin (Wan 2018). One block in these networks is apparently adequate for normalization, in contrast to the 3-5 blocks required for other tumor cell networks. Behavioral changes, such as weight loss, exercise, a healthier diet and reducing alcohol and tobacco use may also be therapeutic by either altering hormone levels or changing their interaction with other risk factors.
7. Antagonize germline changes that promote malignant behavior. Genetic testing of nontumor cells (germline testing) is recommended for all patients with pancreatic cancer (Stoffel 2019) and select patients with other cancers or family histories of cancer (Daly 2020, Lincoln 2020). Results are currently used to determine antitumor therapy (Zhu 2020) as well as for cancer screenings, reproductive choices and genetic counseling. We suggest using these results to also provide treatment that: (a) moves premalignant or malignant cells into less harmful pathways as discussed in Part 5; or (b) counters common germline changes in inflammatory, DNA repair, cell cycle stability, immune system or other networks that promote malignancy.
These blog essays have summarized proposed strategies for curative cancer therapy. The next essay will discuss random chronic stress, a newly proposed major factor in how cancer arises that cannot be prevented but can be better understood.
Curing Cancer – Part 5 – Key network issues that affect the primary tumor
17 January 2021, revised 19 June 2022, click here.
This is my fifth essay about curing cancer based on the principles of complexity theory (follow my blog at https://natpernickshealthblog.wordpress.com). This essay discusses key network issues for curative treatment that affect the primary tumor.
1. Kill as many tumor cells as possible. High tumor cell kill is important because: (a) tumor cells directly damage cells, tissue and organ systems, interfering with their physiologic functions which maintain life; (b) tumor cells create an increased workload, both by producing biologic substances that interfere with optimal physiology and by stimulating a response to destroy them; and (c) tumor cells have molecular heterogeneity so killing each tumor cell may destroy a different strategy used by the tumor cell and its progeny to overcome the body’s antitumor defenses.
2. Attack multiple targets within local tumor networks. Curative treatment for adult tumors should build on our success in curing cancer in children and young adults, including childhood leukemia, Hodgkin lymphoma and testicular cancer. These cancers are caused by inherited or constitutional cancer predisposition or developmental mutations (Kentsis 2020) and exhibit a limited number of somatic (acquired) tumor mutations (Sweet-Cordero 2019). Although they typically have no prominent risk factors and show no field effects (widespread premalignant or malignant changes), curative therapy still requires combinations of 3-5 effective treatments, each with different mechanisms of action, mixed and matched for maximum effect (Mukherjee: The Emperor of All Maladies 2010). Multiple antitumor agents are necessary because biological pathways are not strictly linear. Rather, they are weblike, allowing cancer cells to bypass important steps blocked by antitumor agents (Nollmann 2020, Ozkan-Dagliyan 2020). Curing adult cancers may require even more treatment diversity due to: (a) their complex and heterogeneous mutational landscape (de Sousa 2018, Blank 2018, Samuel 2011), (b) the field effects generated by cancer promoters / risk factors acting over decades of exposure and (c) associated systemic network changes that must also be addressed by treatment (to be discussed in the next essay, Part 6).
Drug combinations may be more effective than single agents due to synergy, the interaction of two or more substances producing a combined effect greater than the sum of their separate effects (Mokhtari 2017). Determining whether drug combinations are synergistic, additive or antagonistic is time consuming, but “deep learning,” other computational approaches and modeling methods may help screen possible combinations for effectiveness (Kuenzi 2020, Sidorov 2019). Combining different types of therapy may also be effective; for example, regional hyperthermia combined with radiotherapy may kill cancer stem cells (Oei 2017), be synergistic with immune checkpoint inhibitors (Li 2020) and improve survival (Fiorentini 2019).
3. Move local tumor cell networks into less lethal states. Curative treatment, in addition to killing large numbers of tumor cells through multiple mechanisms, should “normalize” or reduce the malignant traits of tumor cells that survive (Heudobler 2019). Fifty years ago, Kauffman discovered that a complex network of thousands of mutually regulating genes in normal cells may produce a stable equilibrium state called an attractor that corresponds to gene expression profiles specific to each cell type (Kauffman 1969, Noble 2015). Essentially, the environment of biological substances forces them to have similar behavior even though they behave very differently when isolated. Attractors have been analogized to a low energy state or valley on a topographic diagram that pulls in cells with similar network configurations (Waddington 1957). See diagrams at Vallacher 2013, Goldberg 2007.
Attractors maintain cellular network stability against common disruptions in both normal cells and cancer cells. In normal cells, this stability may be disturbed by cancer “super promoters” (risk factors), acting over long time periods, that push cell networks into malignant pathways. In cancer cells, these “cancer attractors” create network stability that makes tumor cells resistant to antitumor treatment (Huang 2009, Pernick 2020).
Curative antitumor treatment problems should push tumor cells that survive the treatment towards alternative states with reduced malignant properties. Examples include retinoids for acute promyelocytic leukemia and childhood neuroblastoma (Nowak 2009), progestin for endometrial hyperplasia, a premalignant condition (Gallos 2013) and other lineage reprogramming agents (McClellan 2015, Gong 2019). Constant disturbing of parts of the network may also be useful (Cho 2016, Kim 2017).
The next essay will discuss key systemic network issues that affect cancer cells by acting outside of the primary tumor.
Curing Cancer – Part 4 – Principles of curative treatment
10 January 2021, revised 19 June 2022, click here.
This is my fourth essay about curing cancer based on complexity theory – follow my blog at https://natpernickshealthblog.wordpress.com. In part 3, I summarized my recommendations on curative treatment for advanced adult cancers with a poor prognosis, such as lung and pancreatic cancer. In this essay, I discuss the principles of curative treatment in greater depth.
I. Network medicine. Adult cancer is a systemic disease. It arises and is maintained due to dysfunctional cellular networks, not just mutated genes in a simple pathway. A network is defined as a complex set of interactions or relationships between different entities. By contrast, a simple pathway is a linear process with changes that occur one step at a time, such as an automobile assembly line. Scientists often think about biological pathways as a circular assembly line with small changes at each step until the pathway’s function is completed, such as activating an enzyme; then the pathway begins again. Complex biological pathways, such as those related to cell division, interact with each other at many steps, resembling sets of intersecting circles forming a network web of pathways that, when viewed as a whole, may perform a higher level function. The concept of “network medicine” emphasizes this point of view (Barabási 2011, Parini 2020).
Adult tumors may begin with local changes but large tumors are sustained by years or decades of supportive network changes throughout the body, called an altered systems biology (Koutsogiannouli 2013). Even if the tumor is destroyed by surgery, radiation or otherwise, networks outside the tumor typically will not revert to normal and may create new tumors.
II. Blocking multiple pathways. Disabling the activity of some dysfunctional networks requires combinations of treatments to block multiple pathways because these networks interact in a weblike manner and can readily bypass a single block in a particular pathway. The most consistent property of cancer cells is uncontrolled cell division, the target of most anticancer drugs. In the 1940s, Dr. Sidney Farber, a Harvard pathologist, gave his childhood leukemia patients a new drug, aminopterin, which blocked the effect of folic acid, which is needed for cells to divide (Dana-Farber Cancer Institute, accessed 2Jan21). Amazingly, these children, who usually died within weeks of diagnosis, went into remission. But their cancer soon relapsed, most likely because tumor cells bypassed this block through the web of reactions relating to cell division. We now know that it may take 3-5 drugs with different mechanisms of action to create enough blocks to completely disable these specific tumor networks (Mukherjee: The Emperor of All Maladies 2010).
III. Combinations of combinations of treatment. Adult tumors are due to network dysfunction in the local tumor as well as in many key systemic networks affecting the tumor, including inflammation and the immune system and may be promoted by hormones such as estrogen, testosterone or insulin. Normalizing or antagonizing each network may require a distinct treatment or combinations of treatments. Thus, curative therapy that affects all of these networks supporting the tumor may require combinations of combinations of treatment. This is more complicated than for childhood tumors, which are typically caused by inherited mutations (Kentsis 2020) and lack key systemic network changes.
IV. Monitoring key networks. It may be important to target these key networks which nurture and maintain the tumor and to monitor their status as treatment is given: the inflammatory process in general, the immune system’s antitumor capabilities, the microenvironment of the tumor and metastatic sites, unicellular type networks that promote malignant properties, embryonic networks that promote lack of cell differentiation and rapid growth, hormones that promotes tumor growth and germline (inherited) changes that promote malignant behavior directly or indirectly by affecting other networks. These key networks will be discussed in more depth in future essays. This monitoring, analogous to therapeutic drug monitoring of antibiotics and other antimicrobials for infectious diseases, should supplement existing radiologic and clinical studies that determine the size and extent of the known tumor. For each network, we must determine what biological molecules to monitor, how best to do so and how changes in their values should affect treatment. It may be useful to develop a cancer network score analogous to the TNM staging score for tumors that predicts prognosis and suggests future treatments.
V. Clinical trials. Extensive clinical trials will be needed to determine the effectiveness of individual treatments, combinations of treatments and combinations of combinations of treatments affecting these key networks. Additional studies will determine how to reduce side effects and what adjustments to make for particular patients. Towards this end, every cancer patient should be enrolled in a clinical trial.
VI. Strong public health programs. A curative treatment strategy includes strong public health programs to promote cancer risk reduction, effective screening programs and ensuring that all patients get adequate medical care. Risk factor reduction includes behavioral changes such as reducing smoking, excess weight and alcohol abuse and encouraging a healthy diet and exercise (European Code Against Cancer, accessed 2Jan21). At a societal level, our public health and medical care systems act as a behavioral immune system (Schaller 2015) to reduce cancer risk factors. Our physiologic immune system prevents numerous cancers from being clinically evident, as demonstrated by the high cancer rate in immunosuppressed patients due to drugs, diseases (HIV) or genetic disorders. Similarly, a well run public health system that promotes risk factor reduction and early detection prevents many cancers from arising. We should also develop more effective programs for identifying premalignant or malignant lesions in both high risk patients and current patients being monitored for relapse. At an individual level, optimal medical care promotes the reduction of behavioral risk factors, earlier detection of disease and increased use of effective treatments not available to those with inadequate care, poor performance status or severe comorbidities (Kelly 2016, Maclay 2017).
The next essay will discuss the key treatment issues affected by these principles in more detail.
Curing Cancer – Part 3 – Curative cancer treatment based on complexity theory
29 December 2020, revised 19 June 2022, click here.
This is my third essay about curing cancer using the principles of complexity theory. It outlines my recommendations for curative treatment for advanced adult cancers with a poor prognosis, such as lung and pancreatic cancer.
Curative treatment should address the following principles:
I. Network medicine. Adult cancer is a systemic disease. It arises and is maintained due to dysfunctional cellular networks, not just mutated genes. Advanced disease is due to an altered systems biology (Koutsogiannouli 2013) with changes in networks beyond the tumor that typically will not revert to normal if the tumor is destroyed. Thus, focusing on “network medicine” is mandatory (Barabási 2011).
In contrast, cancer in children and young adults may not be a systemic disease because it is due to inherited or developmental mutations that primarily affect only the tumor cells (Kentsis 2020). Unlike adult cancer, it is not due to risk factors and there may be minimal involvement of the inflammatory system, immune system and hormonal pathways (Curing Cancer – Part 2).
II. Blocking multiple pathways. Disabling the activity of a dysfunctional network often requires drug combinations because networks interact in a weblike manner and can readily bypass a single block in a particular pathway. For cancers of children and young adults, curative treatment typically requires at least 3 to 5 drugs to block pathways sufficiently to disrupt the cancer network (Mukherjee: The Emperor of All Maladies 2010).
III. Combinations of combinations of treatment. Since adult tumors are due to dysfunction in many key systemic networks (see below), each often requiring a different set of combinatorial therapies, curative therapy may involve combinations of combinations of treatment.
IV. Monitoring key networks. To optimize treatment, it is important to monitor the status of these key networks as treatment is given: the inflammatory process in general, the immune system’s antitumor capabilities, the tumor’s microenvironment, unicellular type networks that promote malignant properties, embryonic networks that promote lack of cell differentiation, hormonal expression that promotes tumor growth and inherited changes that promote malignant behavior. For each of these networks, we must determine what biological molecules to monitor, how best to do so, how changes in their expression should affect treatment and how these values will impact long term survival rates.
V. Clinical trials. Extensive clinical trials will be needed to determine the effectiveness of individual treatments, combinations of treatments and combinations of combinations of treatments against these key networks, as well as their effect on tumor growth and long term survival rates. Additional studies will determine how to reduce side effects and what adjustments to make for particular patients. Towards this end, every cancer patient should be enrolled in a clinical trial, a major change in the status quo.
VI. Public health and preventative programs. A curative treatment program should attempt to reduce personal behavior that promotes malignancy, such as tobacco use, excess weight and alcohol abuse; develop better screening programs to identify premalignant or malignant lesions in both high risk patients and current cancer patients being monitored for relapse; and promote strong public health programs that encourage risk factor reduction and ensure that all patients get adequate medical care.
Key network issues to be addressed by curative treatment are:
1. Kill as many tumor cells as possible.
2. Attack multiple targets within local tumor cell networks.
3. Move local tumor cell networks into less lethal pathways.
4. Disrupt the inflammatory process, which plays a central role in promoting and sustaining carcinogenesis.
5. Disrupt the microenvironment that nurtures tumor cells at primary and metastatic sites.
6. Disrupt the microenvironment that promotes an embryonic phenotype in some tumors, which is associated with aggressive tumor behavior.
7. Repair immune system dysfunction that coevolves with carcinogenesis.
8. Promote the activation of gene networks supporting stable, multicellular processes and suppress networks promoting unicellular processes that support malignant type behavior.
9. Antagonize hormonal expression that promotes tumor growth.
10. Antagonize inherited genetic changes that promote malignant behavior.
Future essays will discuss these principles and network issues in depth.
Curing Cancer, Part 2 – Adult versus childhood cancer
This is my second essay about curing cancer. See also Curing cancer, Part 1 – Reductionism vs. Complexity. Click here for an update in April, 2022.
The top 10 causes of US cancer death for all ages are listed below, including the projected number of deaths in 2020 and the 5 year relative survival rate (see Cancer Facts & Figures 2020 for all cancer related statistics). The 5 year relative survival rate is the number of patients alive at 5 years after diagnosis, with or without cancer, divided by the number of patients of a similar age expected to be alive who do not have cancer, based on normal life expectancy. Note that 5 year survival is not necessarily a cure – some patients may relapse.
#1 Lung cancer, 135,720 deaths, 5 year survival 19%
#2 Colon cancer, 53,200 deaths, 5 year survival 64%
#3 Pancreatic cancer, 47,050 deaths, 5 year survival 9%
#4 Breast cancer, 42,690 deaths, 5 year survival 90%
#5 Prostate cancer, 33,330 deaths, 5 year survival 98%
#6 Liver cancer, 30,160 deaths, 5 year survival 18%
#7 Non Hodgkin lymphoma, 19,940 deaths, 5 year survival 72%
#8 Central nervous system cancer, 18,020 deaths, 5 year survival 34%
#9 Bladder cancer, 17,980 deaths, 5 year survival 77%
#10 Esophageal cancer, 16,170 deaths, 5 year survival 20%
These top 10 cancers are projected to cause 414,260 deaths or 68.3% of the total projected US cancer deaths in 2020.
Cancer in children differs from cancer in adults. Children have far fewer cases (11,050 versus 1.8 million), fewer deaths (1,190 versus 606,520), different histologic (microscopic) types and higher rates of 5 year survival:
Central nervous system cancer, 74%
Ewing sarcoma, 76%
Hodgkin lymphoma, 98%
Leukemia, 87% (91% for acute lymphocytic leukemia, 66% for acute myeloid leukemia)
Neuroblastoma, 81%
Non Hodgkin lymphoma, 91%
Osteosarcoma, 69%
Retinoblastoma, 96%
Rhabdomyosarcoma, 71%
Testicular lymphoma, 95%
Wilms tumor, 93%
Cancer survival rates are higher in children than adults because their tumors have different origins and because clinical trials are more commonly used.
Childhood tumors are typically caused by inherited or constitutional cancer predisposition or developmental mutations (Kentsis 2020), are not age related and show no “field effects” (large areas affected by premalignant or malignant change). In contrast, adult tumors are caused by risk factors acting over decades, including tobacco use and exposure to other carcinogens, alcohol use, excess weight, Western diet (high fat, few vegetables), microorganisms and parasites, constant hormonal exposure and immune system dysfunction. Adult tumors are associated with older age and show prominent field effects. For example, the average age for lung cancer patients is 70 years and many of these patients have premalignant and malignant lesions throughout their lungs because cigarette smoke damages cells throughout the respiratory tract.
There is a strong emphasis on enrolling every child with cancer in a clinical trial to compare current standard therapy for a particular risk group with a potentially better treatment that may improve survival or reduce treatment side effects. As a result, children with leukemia are sorted into different risk categories and treatment plans based on age, gender, weight, race / ethnicity, central nervous system involvement, testicular involvement, white blood cell count, characteristics of leukemic cells and genomic alterations (NCI: Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version, accessed 6Dec20).
Curing childhood tumors requires combining multiple effective treatments with different mechanisms of action (Mukherjee: The Emperor of All Maladies 2010). Often, “combinations of combinations” of treatment are needed to kill all tumor cells, even though these tumors may originate from just one mutation in one cell. Combining treatments is necessary because biologic pathways are weblike, not linear. This means that treatment directed at stopping one dangerous pathway may be ineffective because the tumor uses alternative pathways on the biologic “web” to achieve a similar function (Nollmann 2020).
To cure adult tumors, more combinations may be required than for childhood tumors because adult tumors originate from many mutations in many cells, due to multiple risk factors acting over long periods of time. Clinical trials are important because human physiology follows the principles of self-organized criticality, which indicate that we cannot easily predict the impact of treatment combinations. This is analogous to the difficulty in predicting changes in a sandpile as grains of sand are added (Bak, How Nature Works 1999, Pernick 2017). The only way to effectively test whether treatment combinations are effective and tolerable in different patient groups is with clinical trials.
It is also important to address the many systemic changes related to adult tumors that occur in the decades it takes for the tumor to arise. This will be discussed in a future essay.
Curing Cancer, Part 1 – Reductionism versus Complexity
Click here for an update in April, 2022.
In 1971, President Richard M. Nixon announced the beginning of the US “war on cancer” (see President Nixon’s 1971 State of the Union at 15:03). Despite massive government expenditures (Kolata: Grant System Leads Cancer Researchers to Play It Safe, New York Times, 27Jun09) and testimonials that the war on cancer “did everything it was supposed to do” (NCI: National Cancer Act of 1971, accessed 10Nov20), cancer is still a leading cause of death (Centers for Disease Control and Prevention 2016, Cancer Statistics 2020), with high mortality from cancer of the lung, colon, pancreas and breast (Cancer Facts & Figures 2020).
Our war on cancer has failed because our basic approach to biology is wrong. Biologic thinking has traditionally relied on reductionism, the theory that the behavior of the whole is equal to the sum of the behavior of the parts. Based on this theory, sophisticated systems are presumed to be combinations of simpler systems that themselves can be reduced to simpler parts (Mazzocchi 2008), disease is due to flawed parts and treatment needs to merely identify and repair the damaged parts. Although logical and rational, reductionism does not actually describe how complex systems function.
In complex systems, the properties of the entire system are greater than the sum of the properties of each part due to interactions between the parts (Kane 2015). Novel properties emerge from the parts and their interactions if one views the entire system as a whole. For example, start with a large number of biological molecules (proteins and other organic compounds), each relatively inert by itself, but capable of interacting in different ways with each other. Then confine them to a small space to promote these interactions. The result may be a living system, a self-sustaining web of reactions that can reproduce and evolve, properties that could not be even imagined by studying each part (Kauffman 1993, Pernick 2017).
Other examples of complex systems include communities formed by individuals and electric grids composed of individual power plants. In each complex system, the result is more dynamic and intricate than could be predicted from studying each component.
Complex systems often exhibit self-organized criticality, the tendency of large systems with many components to evolve to a critical state or “tipping point” (Bak, How Nature Works 1999). When dropping individual grains of sand onto a surface, each grain typically just adds to a growing sandpile. Occasionally, it triggers a small avalanche of the sandpile. Less frequently, it triggers a larger avalanche, and rarely, it causes the entire sandpile to collapse. What is different about the grain of sand that triggers an avalanche from the grain of sand that just sits there? Surprisingly, there is no difference. The grain that appears to do nothing causes subtle structural changes in the sandpile, promoting an eventual collapse after enough grains are dropped. Although we focus on each grain as being important to the outcome, the functional unit is the sandpile itself.
Similarly, cellular networks composed of biologic molecules, cells, tissues and organs are poised at a critical state in which small perturbations typically cause no change but occasionally cause small network changes. Rarely, a trivial event sets in motion a large systemic response, leading to a major reconfiguration of the system (Bak, How Nature Works 1999), such as initial steps towards malignancy. Although cancer scientists tend to focus on initial or “driver” mutations, complexity theory suggests that we should focus on the cellular networks as the functional units.
The human body is composed of a myriad of interacting networks positioned at critical states, which is required for network flexibility to enable embryonic development, the inflammatory response to trauma and infection and the capability for our species to evolve to a changing environment. However, the tradeoff for maintaining these critical states is that cancer, a type of catastrophic systemic failure, is inevitable. We can reduce its incidence, we can detect it earlier and we can treat it more effectively but attaining a “world without cancer” (American Cancer Society, accessed 13Nov20) is not possible.
End of Part 1
Nat Pernick's Curing Cancer Blog 