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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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At a glance
WHAT IT’S REALLY ABOUT
Lew Cantley on Insulin, Sugar, PI3K Inhibitors, and Cancer Metabolism
- Cantley describes how insulin activates PI3K, the same enzyme many oncogenes use, which led him to conclude that insulin resistance and high insulin accelerate tumor growth.
- His lab found that mice drinking a sugary liquid containing both glucose and fructose grew larger colorectal polyps, because fructose reaches the colon and lowers ATP so glucose carbon is diverted into building tumor mass.
- PI3K alpha inhibitors cause hyperglycemia, and the resulting insulin surge can reactivate PI3K in tumors, so Cantley's team showed that lowering insulin with a ketogenic diet or SGLT2 inhibitor made the inhibitors work much better in mouse cancer models.
- Cantley and Attia discuss his companies Petra and Faeth, which aim to test an SGLT2 inhibitor plus PI3K inhibitor trial and to provide standardized meals as part of cancer therapy.
- In an appendix, Cantley recounts how an unexpected lipid-kinase activity, a one-millimeter shift on a thin-layer plate, and a mislabeled reagent led to discovering PI3K and its products.
IDEAS WORTH REMEMBERING
5 ideasUnexpected results are where breakthroughs come from
Cantley says he gravitates to results that don't fit the simple explanation, and he urged his student to chase the surprising pyruvate kinase finding rather than dismiss it as boring.
The Warburg effect can reflect carbon diversion, not broken mitochondria
Cantley and colleagues proposed that cancer cells regulate glycolysis to divert intermediates into building lipids, serine, and nucleotides while mitochondria keep functioning.
Insulin, not just body weight, may be the key driver of cancer risk
Cantley cited a breast cancer study in which insulin-sensitive overweight women had no increased risk, while insulin-resistant women, including lean ones, did, and he argued BMI is a poor correlate.
Sugary liquids with glucose plus fructose can feed colorectal tumors directly
In mice given a small amount equal to a 12-ounce soda without obesity, polyps still grew two to three times larger because fructose reached the colon and phosphorylation by ketohexokinase drained ATP, letting glucose flood anabolic pathways.
PI3K inhibitors fight an insulin rebound
Alpha-isoform inhibitors raise glucose, prompting insulin release that reactivates PI3K, so Cantley insisted trial patients not be managed with insulin or insulin secretagogues, and about half could not be managed on metformin alone.
WORDS WORTH SAVING
5 quotesSerendipity in science is absolutely critical that when you get a result that's unexpected, you should be laser-focused on understanding at the biochemistry, at the chemical level why you got the different result than you expected to get.
— Lew Cantley
If I get a result that suddenly doesn't make sense, to me that's more exciting. It means there's something more complicated going on than the simplest explanation for what I'm seeing.
— Lew Cantley
In order to try to always challenge people in my lab to prove me wrong rather than prove me right, and because it's always learned more if my simplest idea is wrong.
— Lew Cantley
Most endocrinologists worry about the glucose. I worry about the insulin.
— Lew Cantley
If we don't convert those observations into actual change in behavior or change in practice or change in drug metabolism and diet, then in the end we've failed.
— Lew Cantley
High quality AI-generated summary created from speaker-labeled transcript.
