← The Peter Attia Drive

#62 - Keith Flaherty, M.D.: Deep dive into cancer—History of oncology, novel approaches to treatment, and the exciting and hopeful future

Jul 15, 2019 2h 57m 42 insights
<p>In this episode, Keith Flaherty, director of clinical research and targeted cancer therapy at Massachusetts General Hospital, shares his vast wealth of knowledge in cancer starting with the history of treatment from chemotherapy to radiation to surgical therapy and where those methodologies seemed to have leveled off. He also walks us through the timeline of advancements (and lack there of) from when the War on Cancer was declared in the 1970s, through the sequencing of the entire human genome, and all the way to today. Keith dives into the topic of immunotherapy, probably the most exciting recent development in cancer therapy, and also provides us a rundown of his notion of a different approach to cancer that attacks all the essential pillars of cancer growth and survival. Finally, we talk a little bit about liquid biopsies, we discuss the roles of CRISPR and other potentially over-hyped therapies with respect to cancer. We also touch on stem cell therapy a bit, as well as some other common cancer-related questions such as the role of vitamin D and sun exposure in melanoma, and much more.</p> <p><span> We discuss:</span></p> <ul> <li>Growing up around medicine, and finding a career that you love [7:30];</li> <li>Medicine as a career, limitations of the med school teaching approach, and the dynamic and accelerating field of medicine and technology [16:30];</li> <li>Explaining chemotherapy, radiation, and how a cancer develops [23:45];</li> <li>Surgical oncology, cure rate of solid tumors, and survival rate after tumor removal  [33:15];</li> <li>25 years after the War on Cancer is declared, gene sequencing, and why Keith's was fascinated by the HIV case study [37:15];</li> <li>Cancer immunotherapy: History, how it works, and why some cancers respond and others don't [46:00];</li> <li>MHC complexes, and cancer cloaking mechanisms [56:00];</li> <li>Comparative biology of cancer: Why some cancer can evade immune detection better than others [1:03:00];</li> <li>What we learned from the Cancer Genome Atlas Project [1:07:00];</li> <li>Defining targeted therapy, HER2 breast cancer, chronic leukemia, and the translocation of chromosomes [1:12:00];</li> <li>Tumor protein P53, the most famous tumor suppressor gene and its ubiquity in cancer [1:17:45];</li> <li>Activated oncogenes, the RAS pathway, PI3 kinase, RAF gene, and Keith's "aha moment" [1:24:15];</li> <li>Advice for starting your career as a scientist/clinician [1:37:00];</li> <li>Fusion-driven cancers, targeted therapy, and the Bcr-Abl/chronic myelogenous leukemia case study [1:39:45];</li> <li>Targeted therapy for fusion-driven solid tumors, adjuvant systemic therapy, and the HER2 breast cancer example [1:53:00];</li> <li>Advancing melanoma treatment, survival, and cure rates with BRAF-MEK combo therapy [1:59:15];</li> <li>The fundamental pillars of cancer growth and survival, and the toolkit we need to attack cancer from all angles [2:02:40];</li> <li>Peter's clinical framework for thinking about cancer and how Keith might improve it, and how the biotech environment is hampering our ability to put together novel cancer treatments [2:05:00];</li> <li>How useful is CRISPR in terms of tumor suppressing? [2:16:15];</li> <li>Liquid biopsies as a therapeutic monitoring tool [2:18:00];</li> <li>Stem cell therapy: The efficacy and potential risks [2:25:15];</li> <li>Aging and cancer: Is cancer inevitable? [2:28:45];</li> <li>Vitamin D supplements, sun exposure, melanoma, and exercise [2:32:30];</li> <li>How and why Keith has straddled the line between science/research and industry/drug companies, and the importance of getting more voices of practitioners at the table [2:42:00]; and</li> <li>More.</li> </ul> <p><span style="white-space: pre-wrap;">Learn more at <a href="http://www.peterattiamd.com/">www.PeterAttiaMD.com</a><br /> Connect with Peter on <a href="Facebook.com/PeterAttiaMD">Facebook</a> | <a href="Twitter.com/PeterAttiaMD">Twitter</a> | <a href="Instagram.com/PeterAttiaMD">Instagram</a>.<br /></span></p>
Actionable Insights

1. Minimize Cancer Risk Factors

Actively reduce known cancer risk factors such as smoking, insulin resistance, and obesity, as these contribute significantly to cancer development.

2. Prioritize Exercise for Health

Engage in regular exercise for its profound health benefits, recognizing it may be a significant confounder in studies attributing benefits solely to sun exposure or vitamin D.

3. Pursue Aggressive Early Detection

Utilize advanced and layered diagnostic technologies (e.g., MRI, ultrasound, molecular screening) to detect cancer at its earliest, sub-clinical stages, potentially before it becomes clinically relevant.

4. Utilize Liquid Biopsies Early

Embrace liquid biopsies (circulating tumor DNA/RNA) as a non-invasive method for early cancer detection, potentially identifying tumors smaller than what traditional imaging can find.

5. Practice Sun-Safe Exercise Habits

If exercising outdoors, choose sun-safe times (early morning or evening) to minimize UV exposure and reduce skin cancer risk, especially for individuals with a history of melanoma.

6. Avoid Excessive Mid-Day Sun

Limit sun exposure during peak hours to reduce the risk of skin cancer, even while acknowledging potential benefits of sun-seeking behavior, as evolutionary pressures for sun exposure are maladapted for modern longevity.

7. Supplement Vitamin D Wisely

Maintain adequate vitamin D levels through supplementation if sun exposure is minimized (e.g., exercising indoors or during sun-safe times) to potentially reduce cancer risk, as low vitamin D levels are associated with various cancers.

8. Utilize Adjuvant Therapy Effectively

Employ adjuvant systemic therapies, even if they show modest effects in overt metastatic disease, to target microscopic residual disease after surgery, significantly improving cure rates in some cancers like HER2-positive breast cancer.

9. Employ Combination Targeted Therapy

For cancers with known oncogene drivers, use combination targeted therapies (e.g., BRAF and MEK inhibitors in melanoma) to overcome resistance mechanisms and achieve higher cure rates, especially in the adjuvant setting.

10. Prioritize Early Cancer Treatment

For genetically simple cancers driven by specific fusions (like CML), early and targeted single-agent therapy can lead to deep and durable responses, but delaying treatment allows for genetic evolution and resistance.

11. Advocate Multi-Pillar Cancer Therapy

Push for the development and clinical testing of combination therapies that simultaneously target multiple fundamental pillars of cancer (e.g., immune system, oncogenes, epigenetics, metabolism) for more effective and durable outcomes.

12. Monitor Therapy with Liquid Biopsies

Use liquid biopsies as a tool to monitor the effectiveness of cancer therapies, tracking minimal residual disease and informing decisions on when to stop or switch treatments.

13. Leverage Immunotherapy for Cancer

Explore immunotherapy options, such as checkpoint inhibitors, which can unleash the body’s immune system to recognize and attack cancer cells, particularly in immunogenic tumors like melanoma and renal cell carcinoma.

14. Seek Precision with Targeted Therapies

Advocate for and utilize targeted therapies that are specifically designed to inhibit known cancer-driving mechanisms, moving beyond broad-spectrum chemotherapy to more precise interventions.

15. Target Epigenetic Regulators

Focus on developing and utilizing therapies that target epigenetic regulators, as these are crucial for cancer cells’ plasticity and ability to adopt abnormal programs for survival and metastasis.

16. Exploit Oncogene Addiction

Target activated oncogenes that cancer cells are ‘addicted’ to, understanding that inhibiting these single molecules can disrupt multiple essential cancer programs, while normal cells can compensate.

17. Continuously Adapt Career Skills

In rapidly advancing fields like medicine, continuously learn new skills and adapt to technological changes, such as understanding computational biology, to remain relevant over a multi-decade career.

18. Prioritize Investigative Thinking

Cultivate an investigative mindset to identify the boundaries between known and unknown, and focus on operating at that frontier to advance knowledge and patient care, as this is not typically taught in medical school.

19. Mentor Future Generations

For established professionals, actively mentor younger generations, guiding them to acquire interdisciplinary skills like computational biology, which are crucial for future success in evolving fields.

20. Engage in Entrepreneurial Roles

Clinical investigators should consider entrepreneurial roles, such as co-founding companies, to ensure that scientific hypotheses are tested with integrity and patient benefit remains central to drug development decisions.

21. Seek Clinician Board Representation

Advocate for and pursue board positions in biotech and pharma companies to bring a patient-level, clinical translational perspective to strategic decisions, ensuring that development paths prioritize meaningful patient outcomes.

22. Advocate Diagnostic-Therapeutic Alignment

Push for better alignment and integration between diagnostic and therapeutic development in cancer, ideally through prospective pairing, to ensure that precision medicine tools are developed and reimbursed effectively.

23. Understand Industry Constraints

For academic researchers, especially clinical investigators, develop a deep understanding of industry’s business models, economic constraints, and development timelines to be more effective collaborators and advocates for patient-centric research.

24. Seek Purpose-Driven Career

Pursue a career path that directly helps people and aligns with personal values, as this can provide deep satisfaction and motivation, making it easier to stay engaged and passionate.

25. Observe Parental Work Ethic

Pay attention to how parents or mentors approach their careers; observing their passion and dedication can inspire a similar commitment and focus on results in one’s own professional life.

26. Embrace Seasonal Changes

Utilize seasonal changes, particularly colder weather, to encourage staying indoors, focusing on work, and taking necessary breaks, which can foster resilience and productivity.

27. Utilize Detailed Show Notes

Refer to comprehensive show notes for additional information, links to studies, and semantic explanations, especially for technical or challenging topics, to deepen understanding.

28. Jump to Specific Podcast Sections

If short on time and interested in specific topics, check the podcast description or listen for host cues to jump ahead to relevant sections, such as the 20-minute mark for cancer discussions.

29. Listen at Higher Speed

If the podcast pace is slow, consider listening at a slightly higher speed to cover more content efficiently, especially for longer episodes.

30. Support Content for Unbiased Info

Consider supporting content creators directly through subscription models to ensure they can provide information without the influence of advertising, fostering trust and authenticity.

31. Access Exclusive Member Content

Become a member to gain full access to exclusive show notes, downloadable transcripts, and participate in Ask Me Anything (AMA) episodes, which can be particularly useful for technical topics.

32. Leverage Member Product Deals

Utilize member benefits to get the best deals possible on products that the content creator genuinely loves and recommends, rather than those from advertisers.

33. Understand Chemotherapy Limits

Recognize that conventional chemotherapy primarily targets rapidly dividing cells, leading to significant side effects and limited efficacy in many solid tumors due to cancer cells’ inherent resilience and adaptive capabilities.

34. Appreciate Local Therapy Limits

While surgery and radiation are effective for local cancer control, acknowledge their limitations in addressing systemic or microscopic metastatic disease, necessitating additional systemic therapies.

35. Recognize Cancer’s Resilience

Understand that cancer cells are highly evolved to survive harsh environments, evade the immune system, and adapt to therapies, which explains the difficulty in treatment and the need for multi-pronged approaches.

36. Be Aware of Immunotherapy Risks

Understand that unleashing the immune system can lead to severe autoimmune side effects, such as gut inflammation from CTLA-4 inhibitors, highlighting the delicate balance of immune regulation.

37. Understand Cancer Stem Cells

Recognize that some cancer cells can revert to a ‘stem cell-like’ state, making them highly resistant to conventional therapies and necessitating different approaches to target these hardy, quiescent populations.

Understand that cancer risk increases with age due to accumulating genetic mutations and declining immune surveillance, making it an almost inevitable outcome if one lives long enough.

39. Recognize Economic Barriers

Understand that the fragmented biotech industry and economic incentives often impede the development and testing of rational combination cancer therapies, requiring systemic changes to facilitate collaboration.

40. Leverage Liquid Biopsies for Specificity

Support the development of liquid biopsy technologies that can fingerprint the cell of origin (e.g., through epigenetic marks) to pinpoint the location of a detected cancer, guiding further investigation and treatment.

41. Learn Bayesian Statistics

Understand Bayesian statistics, as clinical medicine is essentially applying this method to update pre-test probabilities with new information, improving diagnostic accuracy despite potential biases.

42. Optimize Performance, Health, Longevity

Actively seek information and strategies to optimize performance, health, longevity, and critical thinking to live a higher quality, more fulfilling life.