Study of fasting and ketogenic diet reveals a new vulnerability of pancreatic tumors

Good news! Very clever approach to starve a cancer! Cancer is history (soon)!

"... The cancer therapy blocks fat metabolism, which is the cancer's only source of fuel for as long as the mice remain on the ketogenic diet, and the tumors stop growing. ...
Knowing that pancreatic cancer can thrive on fat, and that eIF4E is more active during fat burning, the scientists first placed the animals on a ketogenic diet, forcing the tumors to consume fats alone, and then put them on the cancer drug. In this context, the drug cut off the cancer cells' only sustenance—and the tumors shrank. ..."

"... Different diet-drug combinations will be needed to treat more forms of cancer.

“We expect most cancers to have other vulnerabilities,” ... “This is the foundation for a new way to treat cancer with diet and personalized therapies.” ..."

From the abstract:

"Fasting is associated with a range of health benefits. How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting. We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting. We show that P-eIF4E is responsible for controlling the translation of genes involved in lipid catabolism and the production of ketone bodies. Inhibiting P-eIF4E impairs ketogenesis in response to fasting and a ketogenic diet. P-eIF4E regulates those messenger RNAs through a specific translation regulatory element within their 5′ untranslated regions (5′ UTRs). Our findings reveal a new signalling property of fatty acids, which are elevated during fasting. We found that fatty acids bind and induce AMP-activated protein kinase (AMPK) kinase activity that in turn enhances the phosphorylation of MAP kinase-interacting protein kinase (MNK), the kinase that phosphorylates eIF4E. The AMPK–MNK–eIF4E axis controls ketogenesis, revealing a new lipid-mediated kinase signalling pathway that links ketogenesis to translation control. Certain types of cancer use ketone bodies as an energy source that may rely on P-eIF4E. Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer."

Study of fasting and ketogenic diet reveals a new vulnerability of pancreatic tumors "Scientists at UC San Francisco have discovered a way to get rid of pancreatic cancer in mice by putting them on a high fat, or ketogenic, diet and giving them cancer therapy."

A Ketogenic Diet Could Improve the Response to Pancreatic Cancer Therapy (original news release) "A study of fasting and the ketogenic diet reveals a new vulnerability of pancreatic tumors to an existing cancer drug."

Remodelling of the translatome controls diet and its impact on tumorigenesis (no public access)

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