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#62–Keith Flaherty, M.D.: Deep dive into cancer—History, novel treatments, & the exciting future

Full title: #62–Keith Flaherty, M.D.: Deep dive into cancer— History of oncology, novel approaches to treatment, and the exciting and hopeful future Original release date: 7/15/19 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. We discuss -Growing up around medicine, and finding a career that you love [7:30] -Medicine as a career, limitations of the med school teaching approach, and the dynamic and accelerating field of medicine and technology [16:30] -Explaining chemotherapy, radiation, and how a cancer develops [23:45] -Surgical oncology, cure rate of solid tumors, and survival rate after tumor removal [33:15] -25 years after the War on Cancer is declared, gene sequencing, and why Keith’s was fascinated by the HIV case study [37:15] -Cancer immunotherapy: History, how it works, and why some cancers respond and others don’t [46:00] -MHC complexes, and cancer cloaking mechanisms [56:00] -Comparative biology of cancer: Why some cancer can evade immune detection better than others [1:03:00] -What we learned from the Cancer Genome Atlas Project [1:07:00] -Defining targeted therapy, HER2 breast cancer, chronic leukemia, and the translocation of chromosomes [1:12:00] -Tumor protein P53, the most famous tumor suppressor gene and its ubiquity in cancer [1:17:45] -Activated oncogenes, the RAS pathway, PI3 kinase, RAF gene, and Keith’s “aha moment” [1:24:15] -Advice for starting your career as a scientist/clinician [1:37:00] -Fusion-driven cancers, targeted therapy, and the Bcr-Abl/chronic myelogenous leukemia case study [1:39:45] -Targeted therapy for fusion-driven solid tumors, adjuvant systemic therapy, and the HER2 breast cancer example [1:53:00] -Advancing melanoma treatment, survival, and cure rates with BRAF-MEK combo therapy [1:59:15] -The fundamental pillars of cancer growth and survival, and the toolkit we need to attack cancer from all angles [2:02:40] -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] -How useful is CRISPR in terms of tumor suppressing? [2:16:15] -Liquid biopsies as a therapeutic monitoring tool [2:18:00] -Stem cell therapy: The efficacy and potential risks [2:25:15] -Aging and cancer: Is cancer inevitable? [2:28:45] -Vitamin D supplements, sun exposure, melanoma, and exercise [2:32:30] -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] Show notes page https://peterattiamd.com/keithflaherty/ -------- About: The Peter Attia Drive is a weekly, ultra-deep-dive podcast focusing on maximizing health, longevity, critical thinking…and a few other things. With over 30 million episodes downloaded, it features topics including fasting, ketosis, Alzheimer’s disease, cancer, mental health, and much more. Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan (delay the onset of chronic disease), while simultaneously improving healthspan (quality of life). Learn more: https://peterattiamd.com Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter Connect with Peter on: Facebook: http://bit.ly/PeterAttiaMDFB Twitter: http://bit.ly/PeterAttiaMDTW Instagram: http://bit.ly/PeterAttiaMDIG Subscribe to The Drive: Apple Podcast: http://bit.ly/TheDriveApplePodcasts Overcast: http://bit.ly/TheDriveOvercast Spotify: http://bit.ly/TheDriveSpotify Google Podcasts: http://bit.ly/TheDriveGoogle

Peter AttiahostKeith Flahertyguest

Jan 12, 20202h 57mWatch on YouTube ↗

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WHAT IT’S REALLY ABOUT

Oncologist Keith Flaherty traces cancer therapy from chemotherapy's limits to targeted and immune treatments

Flaherty explains that conventional chemotherapy, radiation and surgery reached an asymptote because chemo kills fast-dividing cells, cures few solid tumors, and tumors have already evolved to survive harsh environments.
The discussion traces how cancer genetics (tumor suppressors, oncogenes, epigenetic regulators) led to targeted therapies, from HER2 and imatinib in Bcr-Abl CML and GIST to BRAF and MEK inhibition in melanoma.
Immunotherapy is covered through checkpoint inhibitors, with cancers like melanoma and kidney cancer being immunogenic and tumors surviving by dialing down antigen presentation and shifting cell state.
Flaherty argues that complex cancers will need multi-drug combinations across several pillars (growth signaling, immune, epigenetic, metabolic), but drugs are scattered across many small biotechs so few rational combinations reach trials.
The conversation also covers liquid biopsies for detection and monitoring, vitamin D and sun exposure in melanoma, and Flaherty's advice for physician-scientists to engage with industry.

IDEAS WORTH REMEMBERING

5 ideas

Chemotherapy plateaued because of how it was discovered

Flaherty says screening for what poisons rapidly dividing cells yielded DNA- and microtubule-disrupting drugs that cure only some testicular cancers, lymphomas and leukemias, while most solid tumors are already hardened by prior selective pressure.

Cancer cells must hide from the immune system to succeed

Tumors that reach clinical size have evaded T cells, and under immunotherapy survivors dial down MHC expression just enough to avoid natural killer cells.

Epigenetic plasticity is a key mechanism of resistance

The Cancer Genome Atlas showed that mutations in epigenetic regulators are common, letting cells open the genomic blueprint and, for example, melanoma cells revert toward a neural-crest-like state after BRAF and PD-1 therapy.

Single targeted drugs help, but combinations cure more

Imatinib worked dramatically in stable-phase CML but only briefly in blast crisis, while BRAF plus MEK inhibition improved on monotherapy in melanoma, and adjuvant treatment of microscopic disease can prevent relapse.

Drug fragmentation is a major barrier to combination therapy

Flaherty says about 60% of new cancer drugs come from small biotechs with one or two assets, and only a tiny fraction of rational combinations find each other in clinical trials; he says regulators and doctors are not the obstacle.

WORDS WORTH SAVING

5 quotes

Medical school teaches information as fact. It teaches the known. That known unknown divide is exactly, it's my pitch in academic medicine, at least talking to people about cancer as a career.

— Keith Flaherty

I think medical school might be one of the most anti-intellectual forms of higher education that exists.

— Peter Attia

If we all live to a hundred and thirty, we'd all have a cancer, quote-unquote, "real cancer."

— Keith Flaherty

We can't keep hitting the same pillar and expect that we're gonna cure cancer.

— Keith Flaherty

You're not waiting for something top secret that someone comes and whispers in your ear.

— Keith Flaherty

Limits of chemotherapy, radiation and surgeryTumor suppressors, oncogenes and epigenetic plasticityTargeted therapy successes (imatinib, HER2, BRAF/MEK)Checkpoint inhibitors and immune evasionCombination therapy and fragmented drug developmentLiquid biopsies and early detectionVitamin D, sun exposure and melanoma

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