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Peter Attia MD#110 – Lew Cantley, Ph.D.: Cancer metabolism, cancer therapies, and the discovery of PI3K
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CHAPTERS
- 0:17 – 8:45
Intro, Disclosures, and Teaching Science Through Discovery
Peter Attia introduces Lew Cantley, explains that the technical PI3K discovery story has been moved to the end, and gives disclosures and a medical disclaimer. The two then discuss teaching science as a story of discovery, with serendipity and unexpected results at the center.
- •The technical discovery segment is moved to the end of the episode as an appendix
- •Lew Cantley's disclosures: Agios, Petra, and the new company Faeth
- •Attia argues science education should focus on discovery rather than rote memorization
- •Cantley says unexpected results are where breakthroughs come from
- 8:45 – 16:58
From Pyruvate Kinase to Cancer Metabolism
Cantley recounts how a graduate student's unexpected pull-down of pyruvate kinase, and the arrival of postdoc Matt Vander Heiden, led to work on cancer metabolism and the founding of Agios. He also describes the history of the Warburg effect and why it fell out of favor.
- •A phosphopeptide pull-down experiment unexpectedly caught pyruvate kinase
- •Two back-to-back Nature papers showed how phosphotyrosine binding turns off pyruvate kinase
- •The Warburg effect fell out of favor as viral oncogenes were discovered
- •Pyruvate kinase activators were proposed as a way to reduce tumor growth
- 16:58 – 20:24
Rethinking the Warburg Effect: Carbon for Growth
Cantley and Attia discuss the 2009 paper's alternative to the 'defective mitochondria' explanation of the Warburg effect. Slowing glycolysis steps diverts intermediates into building blocks rather than ATP.
- •The simple explanation was that mitochondria are defective
- •Regulating glycolytic steps can divert carbon into serine, glycine, ribose and lipids
- •Attia frames it as a carbon-for-construction mass balance argument
- •Cantley uses a river-and-dam analogy
- 20:24 – 26:05
Growing Up in West Virginia and the Rise of Sugar
Attia asks how Cantley's work shaped his own eating habits. Cantley explains that his choices came from watching West Virginia go from lean to obese as sugar became cheap, and how this was before he understood the metabolism.
- •In the 1950s sugar was the most expensive grocery item and few people were overweight
- •Cantley attributes the shift to cheap high fructose corn syrup and sugary drinks
- •He stopped drinking sweet drinks and eating dessert in 1975
- •He describes a real addiction among relatives to sweets
- 26:05 – 32:28
Insulin, PI3K, and Cancer Risk Beyond Obesity
Cantley explains how his work on insulin and PI3 kinase led him to think insulin resistance and high insulin accelerate tumor growth. Attia and Cantley discuss why BMI is a poor proxy and what matters is insulin resistance.
- •Insulin and oncogenes both activate PI3 kinase
- •Insulin has long been added to cultured cancer cells to make them grow
- •Tumors often increase insulin receptor expression
- •Insulin-sensitive overweight women did not show higher breast cancer risk, while insulin-resistant women did
- •BMI is not a good correlate
- 32:28 – 37:55
The Sugar-Water Colorectal Cancer Study in Mice
Cantley describes the Science paper in which mice with APC knockout drank sugary water. Even at a low, non-obesity-causing dose, polyps grew faster, which challenged his insulin-only hypothesis.
- •Ji-A Yun and Marcos Goncalves designed experiments to test the idea
- •Ad lib sugar water caused obesity and much larger polyps
- •A fixed 12-ounce-soda-equivalent dose avoided obesity and insulin resistance but still increased polyps by two to threefold
- •Both glucose and fructose were needed for the effect
- •Liquid transit lets fructose reach the colon
- 37:55 – 47:34
How Fructose Fuels Tumors Through Glucose
The mechanism: fructose is phosphorylated by ketohexokinase, dropping ATP and letting glucose flood anabolic pathways. The fructose drives the kinetics while carbons come from glucose. Cantley then offers an evolutionary explanation for why we crave sugar.
- •Ketohexokinase is found mainly in liver, kidney and gut
- •Phosphorylating fructose consumes ATP, enabling high glycolytic flux
- •Glucose carbons feed fatty acid, serine and nucleotide synthesis
- •Fruit sugars were a seasonal chance to gain weight before winter
- •Hibernating bears illustrate seasonal insulin resistance
- 47:34 – 53:37
Public Policy, Sucrose vs. HFCS, and Whole Fruit vs. Juice
Attia asks whether solutions exist at the policy level, and Cantley points to lessons from smoking, advertising limits, and taxes. They then discuss whether sucrose and high fructose corn syrup differ, and why whole fruit differs from juice.
- •Cantley suggests reducing advertising to children and taxing sugar
- •Sucrose and HFCS made little difference in his experiments
- •Fiber in whole fruit slows absorption and prevents fructose reaching the colon
- •The insulin response can differ even when glucose AUC is similar
- •Cantley says he worries about insulin rather than glucose
- 53:37 – 58:18
PI3K Inhibitors, Hyperglycemia, and the Insulin Problem
Cantley explains why PI3K inhibitors cause hyperglycemia and how reactive insulin can override the drug. He describes working with Novartis to keep patients off insulin, leading to alpelisib's approval.
- •Cantley was skeptical about drugging PI3K without causing diabetes
- •A drug that does not cause hyperglycemia is probably not hitting PI3K
- •Trial patients who needed insulin or secretagogues were taken off the trial
- •Insulin rises after the drug and can reactivate PI3K in tumors
- •Endocrinologists disagreed with him about giving insulin
- 58:18 – 1:08:05
Ketogenic Diet and SGLT2 Inhibitors with PI3K Inhibitors
Cantley describes mouse studies across twelve cancer types combining PI3K inhibitors with ketogenic diet or SGLT2 inhibitors. Both lowered insulin and enhanced tumor shrinkage, though he notes a caution from the AML model.
- •A week of ketogenic diet run-in was most effective
- •SGLT2 inhibitors were almost as effective and easier as a pill
- •Every cancer type studied showed benefit
- •Ketogenic diet alone usually does little
- •The AML model showed some toxicity, so caution is advised
- 1:08:05 – 1:16:27
Petra and Faeth: New Trial and Diet-Drug Pairing
Cantley discloses the upcoming Petra trial pairing an SGLT2 inhibitor with a PI3K alpha inhibitor in stage four breast and endometrial cancer. He also describes Faeth, which plans to make controlled meals, including serine- or methionine-restricted diets.
- •The Petra phase one trial combines an SGLT2 inhibitor with a PI3K alpha inhibitor, and can be found on clinicaltrials.gov
- •Patients will be advised on what to eat for breakfast with the drug
- •Faeth aims to provide standardized meals for cancer patients
- •Serine and methionine restriction may boost some drugs
- •In pancreatic cancer mouse models, diet plus PI3K inhibitor made tumors disappear
- 1:16:27 – 1:22:29
Approved PI3K Inhibitors and Bridging Oncology and Endocrinology
Cantley reviews the approved PI3K inhibitors and their isoform targets. They discuss how specialization separates oncologists and endocrinologists and how food could be prescribed alongside drugs.
- •Alpelisib targets the alpha isoform, approved in May
- •Delta inhibitors like idelalisib work in B cell lymphomas
- •Oncologists and endocrinologists work in silos
- •Attia floats a metabolic oncology specialty
- •Prescribed food would need proof in a phase three trial
- 1:22:29 – 1:27:38
Cantley's Curiosity and Goals for the Next Decade
Asked what question obsesses him, Cantley says he follows unexplained observations across diseases, including epilepsy and PIK3CA mosaic mutations. He wants every lab observation translated into changes in practice.
- •He lets talented trainees pursue what they want and avoids textbook prejudice
- •PIK3CA mutations may be involved in epileptic seizures
- •He plans new papers changing how PI3K regulation is understood
- •His goal is translating findings into clinical practice at Weill Cornell
- 1:27:38 – 1:46:58
Appendix: Origins in Chemistry, Mitochondria, and Insulin Signaling
In the appendix, Attia introduces the PI3K discovery story. Cantley covers his chemistry background, Peter Mitchell and Ephraim Racker's ATP synthesis work, his postdoc with Guido Guidotti, and the discovery that the insulin receptor is a tyrosine kinase like Src.
- •PI3K stands for phosphoinositide 3-kinase, which phosphorylates the 3′ position of inositol
- •Cantley was a pure chemist who avoided biology
- •He saw Mitchell and Racker argue over his thesis data
- •Insulin receptors and growth factor receptors were found to be tyrosine kinases
- •Receptor autophosphorylation left the downstream mechanism unexplained
- 1:46:58 – 2:11:27
Appendix: Discovering PI3 Kinase and the 3-Phosphate Lipids
Cantley describes how a glycerol phosphorylation clue led to PI kinase activity tied to Src, how other labs failed to replicate it without sonication, and how a one-millimeter spot shift revealed the 3-position. The story ends with a mislabeled reagent that exposed PI 3,4,5-P3.
- •Phosphatidylinositol in a membrane was a far better substrate than glycerol
- •Other labs failed because they used detergent rather than sonicated lipid
- •Polyoma middle T mutation showed Src activation alone was not enough to transform cells
- •A one-millimeter alternating migration pattern revealed a different phosphorylation site
- •A mislabeled bottle led to the discovery of PI 3,4,5-trisphosphate
