#62 - Keith Flaherty, M.D.: Deep dive into cancer—History of oncology, novel approaches to treatment, and the exciting and hopeful future
Dr. Keith Flaherty, Director of Clinical Research and Targeted Cancer Therapy at Massachusetts General Hospital, discusses cancer's history, from chemotherapy to immunotherapy, and future approaches like liquid biopsies. He also shares insights on career development for clinician-scientists and common cancer-related questions.
Deep Dive Analysis
21 Topic Outline
Evolution of Medical Careers and Accelerating Technology
Limitations of Chemotherapy and Radiation Therapy
Surgical Oncology and the Asymptote of Local Control
The War on Cancer and the Human Genome Project
HIV Treatment as a Paradigm for Cancer Therapy
Early Immunotherapy: Interleukin-2 and Checkpoint Inhibitors
MHC Complexes and Cancer's Immune Evasion Mechanisms
Insights from the Cancer Genome Atlas Project
Defining Targeted Therapy: HER2 Breast Cancer and CML
The Role of Tumor Suppressor Gene P53
Activated Oncogenes: RAS, PI3 Kinase, and BRAF Pathways
Fusion-Driven Cancers and Targeted Therapy Success
Adjuvant Systemic Therapy for Microscopic Disease
Fundamental Pillars of Cancer Growth and Survival
Challenges in Developing Combination Cancer Therapies
CRISPR's Potential Role in Cancer Treatment
Liquid Biopsies for Early Detection and Monitoring
Stem Cell Therapy and Cancer Risk
Aging and the Inevitability of Cancer
Vitamin D, Sun Exposure, Melanoma, and Exercise
Bridging Academia and Industry in Drug Development
10 Key Concepts
Chemotherapy
This traditional cancer treatment involves agents that primarily tangle DNA or disrupt microtubules, effectively poisoning rapidly dividing cells. While successful for some leukemias and lymphomas, it has shown limited progress against most solid organ metastatic tumors over decades due to its non-specific targeting of fast-growing cells.
Tumor Suppressor Genes
These genes, such as P53, normally act as a cell's sensing apparatus, detecting damage and commanding cell death if damage is catastrophic. When their function is disabled, cancer becomes more likely, as the cell loses its ability to self-regulate and eliminate errors.
Oncogenes
These are genes that, when activated (e.g., through mutation or amplification), promote uncontrolled cell growth and division. Examples include RAS, BRAF, and HER2, which often co-opt normal growth factor signaling pathways to drive cancer's proliferation.
MHC Complex (Major Histocompatibility Complex)
This cellular machinery presents protein fragments (antigens) from inside the cell on its surface, allowing immune cells to survey for foreign or abnormal contents. Cancer cells can evade immune detection by disabling or downregulating MHC complex expression, effectively 'cloaking' themselves.
Targeted Therapy
Unlike conventional chemotherapy, targeted therapy is designed with a specific molecular target in mind, aiming to inhibit or activate a known pathway or protein crucial for cancer growth. This approach allows for more precise intervention, often with fewer side effects than broad-spectrum chemotherapy.
Oncogene Addiction
This concept describes how a cancer cell becomes highly dependent on a specific activated oncogene to drive multiple essential cancer programs, not just proliferation. Inhibiting this single oncogene can therefore have a disproportionately detrimental effect on the cancer cell, while normal cells have compensatory mechanisms.
Epigenetic Regulators
These are proteins that control the folding and unfolding of chromosomes, thereby regulating which parts of the genetic blueprint are accessible and read. In cancer, genetic alterations in these regulators can make cells more 'plastic,' allowing them to adopt programs and behaviors (like metastasis) not normally associated with their cell type.
Fusion-Driven Cancers
These cancers arise from a translocation event where two distinct genetic components join to create a new, abnormal gene product. This often leads to the overexpression of a normal protein, such as the BCR-ABL kinase in Chronic Myelogenous Leukemia (CML), which then drives the cancer.
Adjuvant Therapy
This is systemic therapy administered after primary local treatment (like surgery) when there is no visible cancer, but a high risk of microscopic metastatic disease. The goal is to seek and destroy any remaining cancer cells to prevent recurrence and improve long-term survival.
Liquid Biopsies
These non-invasive diagnostic tools analyze blood samples for circulating tumor DNA, RNA, or cells shed by tumors. They hold promise for early cancer detection, monitoring therapeutic response, and potentially identifying the tissue of origin for occult cancers.
11 Questions Answered
Chemotherapy, developed through a 'blind approach' to kill rapidly dividing cells, has cured only a fraction of testicular cancers, lymphomas, and leukemias, making minimal progress against most solid organ metastatic tumors. Radiation therapy is effective for local control but cannot address systemic disease.
To become a clinically relevant tumor, a cancer cell must overcome numerous selective pressures, including evading the immune system, growing its own blood supply, and surviving adverse metabolic conditions. It must acquire the right genetic alterations to proliferate abnormally and sustain damage, all while remaining 'below the radar' of immune detection.
The immune system uses MHC complexes (Major Histocompatibility Complex) on cell surfaces to present protein fragments, constantly surveying internal cellular contents. If these fragments are recognized as non-self (e.g., from a virus or mutation), T-cells can be activated to destroy the abnormal cell.
Cancers develop 'cloaking mechanisms,' such as disabling or downregulating MHC complex expression, to avoid being seen as foreign by the immune system. The specific genetic and epigenetic makeup of a cancer, and its tissue of origin, can influence its inherent immunogenicity and ability to evade surveillance.
The project's most significant discovery was the widespread occurrence of driver genetic events in genes that regulate chromosomal well-being, often referred to as epigenetic regulators. This revealed how cancers achieve 'plasticity,' allowing them to adopt less differentiated states and perform functions not typical of their normal cell type.
P53 is a master tumor suppressor gene that acts as a sensing apparatus for cellular damage, commanding apoptosis (cell suicide) if damage is catastrophic. While only about 50% of cancers have a direct P53 mutation, the P53 pathway, including its inputs and outputs, is virtually always compromised through other genetic aberrations.
The fundamental pillars include growth factor receptor signaling, epigenetic modulation, immune evasion, and metabolic regulation. Effective cancer treatment often requires a diverse 'toolbox' of therapies that can simultaneously attack multiple of these pillars.
Currently, CRISPR does not offer a foreseeable solution for fixing tumor suppressor genes in cancer. The challenge lies in delivering the gene-editing tool to every single cancer cell, including widely distributed and dormant micrometastases, which is a major logistical and biological hurdle.
Wild-type stem cells are generally assumed to follow normal biological rules, finding their niche and behaving accordingly. Unless they are significantly perturbed in a genetic way, it's unlikely they would go 'rogue' and become cancerous, as they possess robust DNA repair and damage detection mechanisms.
Yes, cancer is considered an inevitable consequence of aging due to the accumulation of too many stochastic genetic events and the breakdown of surveillance systems, including DNA damage repair and immunological mechanisms. If humans lived to 130 years old, it's hypothesized that everyone would eventually develop a 'real cancer.'
While sun exposure increases Vitamin D synthesis, it also increases skin cancer risk. The benefits often attributed to sun exposure may be confounded by exercise, which often occurs outdoors. It's recommended to obtain cardiovascular benefits from exercise in a sun-safe manner (e.g., early morning/evening) and supplement Vitamin D if necessary, as direct supplementation is believed to provide the same benefits without the added UV risk.
42 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.
38. Acknowledge Age-Related Cancer
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.
6 Key Quotes
The blind approach only gave those types of therapies. Those types of therapies then thrown at cancer cure a good fraction of testicular cancer, a respectable fraction of lymphomas and leukemias, and cure almost nothing else.
Keith Flaherty
I think medical school might be one of the most anti-intellectual forms of higher education that exists.
Peter Attia
These things are evolutionary warriors by this point.
Keith Flaherty
If we all lived to 130, we'd all have a cancer, quote unquote, real cancer.
Keith Flaherty
The problem, if I were to put a finger on it, is the way in which companies that decided they could see a business model in HIV and basically decided they were going to pursue it, could create the toolbox within their one company. Had it not been for that, we would not have seen doublet and triplet therapy.
Keith Flaherty
I'm not looking for more work. So this isn't at all about me, but I've seen that as cancer science has become so much more translational, the opportunity unfolded for me. And I think it would be a major benefit to the field for the private sector basically to engage more voices at the table of those who are involved in the truly applied science down to the patient level.
Keith Flaherty