Conceptual vector illustration. Human diseases. Stop cancer
It’s now well established that obesity, visceral (belly) fat and type 2 diabetes (i.e., metabolic dysfunction) increase a person’s risk for developing certain cancers. What is only beginning to be appreciated is that cancer patients that have underlying metabolic dysfunction have much worse outcomes and seriously increased mortality rates. This suggests that metabolic hormones play an important role in cancer progression, and could be valuable targets in cancer treatment.
A variety of chronic, adverse health issues are associated with metabolic dysfunction, including type 2 diabetes, cardiovascular diseases, Alzheimer’s, and most notably – cancer. Metabolic dysfunction is linked with worse outcomes for at least 13 types of cancers and is associated with a 33% elevated risk of death from cancer in the US. Of all the various cancer types, some of the most common are highly sensitive to dysregulated metabolic hormones (insulin, leptin, adiponectin) and chronic inflammation stemming from overweight/obesity, pre-diabetes, type 2 diabetes and metabolic syndrome. An estimated 630,000 patients in the United States alone were diagnosed in 2014 with an obesity-related cancer, including breast, prostate, and colorectal cancers. Yet, only now are oncologists and researchers beginning to pay close attention to the profound influence systemic metabolic dysfunction has on cancer progression and patient outcomes.
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The nexus of cancer and metabolic dysfunction
Metabolic dysfunction leads to dysregulated hormones that impact known oncogenic pathways causing tumors to grow faster with greater metastatic potential, and may even be implicated in cancer treatment resistance. The metabolic hormone insulin, as well as leptin and adiponectin (aka ‘adipokines’), signal through validated oncogenic pathways, including PI3K/Akt/mTOR, MAPK, ERK, JNK, Notch, and STAT3, and trigger deleterious downstream effects such as cell proliferation, migration, angiogenesis, stem cell protection, and metastatic potential. Ultimately, these downstream effects drive tumor growth and metastasis. Moreover, systemic metabolic dysfunction dysregulates the tumor immune microenvironment leading to immune suppression possibly rendering the tumor resistant to cancer treatment.
Sadly, you don’t have to be overweight to have metabolic dysfunction. People who maintain a healthy weight according to their body mass index (or ‘BMI’) can still have systemic metabolic dysfunction, depending on how their body fat is distributed. These individuals are also at a higher risk of developing cancer, one major example of this being in post-menopausal women and breast cancer. Furthermore, cancer therapies themselves can induce metabolic dysfunction (e.g., hyperglycemia, hyperinsulinemia, weight gain, insulin resistance) which can impact the patients’ quality of life and even lead to treatment failure.
Why targeting gene mutations isn’t enough
Current cancer treatments tend to target specific mutations or dysregulated pathways in tumor cells with the goal of blocking cell proliferation and reducing tumor burden. However, as long as metabolic dysfunction is stimulating key oncogenic pathways, oncologists administering these treatments will be fighting a losing battle. Studies with diet and exercise suggest that standard treatments may be more effective if they are administered simultaneously with measures to reduce metabolic dysfunction in cancer patients. This approach addresses the disease on two fronts: molecularly targeted chemotherapeutics arrest cell proliferation and can shrink the tumor size, while restoring normal metabolic hormone levels relieves the external stimulation on oncogenic signaling pathways. Not only does this combination approach impede multiple cancer drivers at both the systemic and cellular levels, but it also improves patients’ quality of life by boosting their strength and possibly lessening side effects from treatment.
It is now more important than ever that standard cancer treatments account for the critical role that metabolic dysfunction plays in patients’ prognosis. Rates of obesity, pre-diabetes and type 2 diabetes are on the rise worldwide, driven by poor diets, sedentary lifestyles, and even reduced activity during the Covid-19 pandemic. Furthermore, metabolic dysfunction and cancer are associated with aging, and retiring baby boomers make up a massive aging segment of our population. This growing population of aging individuals combined with an increase in metabolic dysfunction creates the perfect storm in which many more people are likely to develop highly aggressive forms of cancer in the coming years.
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How to treat a cancer patient with metabolic dysfunction?
When a person with metabolic dysfunction discovers they have cancer, they can work with an endocrinologist or dietician to develop healthier lifestyle habits, such as weight loss, better diabetes control, improved nutrition, and regular physical activity – all of which help the patient better tolerate chemotherapy, and improve the treatment outcomes. However, sticking to a rigorous diet and exercise regimen can be challenging for patients, especially while they are undergoing chemotherapy. While adopting healthy habits should always be a goal, cancer patients could benefit from pharmacological options that treat systemic metabolic dysfunction more predictably and reliably to provide a complementary, “one-two punch” with standard of care cancer therapies so they have a better shot at working. Although there are no drugs on the market specifically targeting this population, the type 2 diabetes drug metformin has been clinically studied in this population, with mixed results.
Treating the patient, not just the cancer
Weinberg’s ‘The Hallmarks of Cancer’ got it right – a multi-faceted approach to treating cancer is the way forward. Metabo-oncology is the emerging area of research dedicated to understanding and developing treatments for cancers that are sensitive to metabolic dysfunction. A steadily-growing body of clinicians are speaking out on the role of metabolic dysfunction and its implications on cancer patient treatment and clinical outcomes.
Justin Brown PhD, assistant professor and director of the Cancer Metabolism Program at the Pennington Biomedical Research Center in Louisiana is a leader in the field researching how metabo-oncology principles can be put into clinical practice. From Dr. Brown’s perspective, the diagnosis of cancer triggers two reactions: on one hand, an individual becomes motivated to do everything in their power to maximize the probability for a good outcome; on the other hand, the diagnosis is overwhelming, stressful, and terrifying. Most patients experience some combination of both reactions, and this is where healthy lifestyle habits can be a powerful, enabling tool.
Dr. Brown believes that oncologists should provide the right information about lifestyle choices to the right patient at the right time. When a patient indicates that they are ready, physicians could then initiate a patient-centered discussion about the benefits of pursuing a healthy lifestyle. Once a patient decides they want to adopt a healthier lifestyle, doctors should put the patients in contact with experts (endocrinologists, dieticians) to help improve clinical success.
In reality, however, while oncologists and their patients generally recognize the importance of healthy lifestyle habits, in a 2019 survey conducted by the American Society of Clinical Oncology, oncologists only reported counselling patients about weight management, healthful eating, and physical activity about 40-60% of the time, due to a lack of training, limited referral options, and lack of third-party reimbursement for diet and exercise counseling.
That’s why treating cancer patients with concomitant metabolic dysfunction remains a major challenge for oncologists. The work of a key opinion leader in this field, Emily Gallagher, MD, PhD demonstrates this well. Dr. Gallagher is an endocrinologist at Mount Sinai in New York who specializes in treating cancer patients with metabolic dysfunction. When Dr. Gallagher treats her patients, she never takes a one-size-fits-all approach to addressing their metabolic issues. Instead, she considers the underlying medical reason patients were referred to her, the type of cancer they have, and the type of treatment they are receiving. She considers pre-existing conditions, like type 2 diabetes, current lifestyle, and disease symptoms when devising a treatment regimen that she believes will be most effective. She sets short-term and long-term goals for her patients and follows up regularly to help keep them on track, and encourages them to see a diabetes educator/dietitian to further encourage positive lifestyle changes.
From Dr. Gallagher’s perspective, when patients have metastatic cancer, their non-cancer background conditions often go under-treated. But, by ignoring systemic metabolic dysfunction, clinical oncologists may inadvertently be contributing to their patient’s disease progression. Therefore, it’s important that oncologists pay close attention to the metabolic health of their cancer patients and monitor for endocrine side effects (hyperglycemia, hyperinsulinemia, obesity/weight gain) induced by the cancer drugs they prescribe. This is why it makes sense to refer these patients to endocrinologists who may have already developed strategies to address these problems. What’s more, by having the oncology team reinforce the importance of systemic metabolic health, it communicates to the patients that their treatment strategy is being administered by a team of doctors using a whole-patient strategy.
While treating physicians know that obesity/systemic metabolic dysfunction leads to worse outcomes for their cancer patients, they face multiple challenges in addressing it: limited pharmacologic interventions that can effectively treat patients’ metabolic issues, lack of training in the methods endocrinologists use to address these issues, and no payer incentives to encourage better lifestyle choices. While we wait for effective pharmaceutical interventions that can reliably address these issues, anti-diabetic medications and diet and exercise will have to do. Addressing systemic metabolic dysfunction in cancer patients requires communication between diverse medical experts and scientific disciplines. Incorporating a multi-disciplined approach to treating cancer should help foster better clinical practices for cancer patients and improved outcomes for patients with cancers sensitive to metabolic hormones.
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James Shanahan is Co-Founder, Chief Business Officer and Director at SynDevRx which is developing pharmaceutical interventions for cancer patients that also have background metabolic dysfunction such as obesity, diabetes, high blood glucose/HbA1c, or insulin resistance. He oversees the development of the company’s business plans, budgets, strategic direction and industry outreach, operations, IP and funding to pursue the Company’s research and development objectives.
Previously, Jim co-founded JAM Technologies, a company that created specialty semiconductors serving the high-end consumer electronics and specialty electronics markets, where he served as vice president of corporate development and on the board of directors. There, he focused on fundraising, executing licensing transactions and forming strategic co-development partnerships, including with AKM, Intel and Apple. Previously, he worked at and later served as a consultant to Ariana Pharmaceuticals, a Paris-based company that provides advanced healthcare data analytics to the pharmaceutical and biotech industry. Jim has numerous issued patents, studied engineering and French at the University of Massachusetts Amherst and studied French at L’Universite Catholique de L’Ouest (Angers, France).
Jim is an active member in the Cambridge biotech and technology communities. He is a member of the BIO trade organization’s Tax and Finance Committee, a mentor at MassBio’s MassConnect, founding member of the French-American Biotech Springboard (FABS), a professional association working under the auspices of the French-American Chamber of Commerce. He is also an active coach and mentor to numerous startups in the Boston/Cambridge area.
