As early as in ancient Greece, philosophers Hippocrates and Plato discussed the health benefits of fasting. Recent research has shown that intermittent fasting, by reprogramming metabolism, shifts the body's energy supply from glucose to ketones, leading to a series of health benefits such as weight loss and reduced inflammation.

Today, the "trendy" ketogenic diet (kD), which also aims to produce ketones, can achieve similar effects to intermittent fasting. The ketogenic diet, a high-fat, extremely low-carbohydrate, and adequate protein diet plan, has been clinically used since the early 1920s. By reducing glucose utilization, the ketogenic diet forces the body to use fat instead of glucose as an energy source, producing ketones through fat breakdown in the liver to fuel life activities.

So far, the ketogenic diet has demonstrated therapeutic effects in various human diseases, including epilepsy, endocrine and metabolic disorders, neurological diseases, COVID-19, and cancer. It is believed to work through multiple mechanisms.

Remarkably, recently, scientists have discovered that the characteristics of fasting and the ketogenic diet can bring new hope for the treatment of pancreatic cancer, the "king of cancers"! In a Nature paper published on August 14, 2024, a team led by Professor Davide Ruggero from the University of California, San Francisco found that feeding mice a ketogenic diet while using a new cancer drug in clinical trials could "starve" tumors in the mice and halt the growth of pancreatic cancer.

This study is the first to find that the eukaryotic translation initiation factor eIF4E alters the body's metabolism during fasting or a ketogenic diet, shifting the body to burn fat for energy. A novel anticancer drug in clinical trials, named eFT508, can block eIF4E and the ketone production pathway, preventing the body from metabolizing fat. In mouse models of pancreatic cancer, combining eFT508 with a ketogenic diet blocked the only energy source for pancreatic cancer cells (fat metabolism), thereby starving the cancer cells.

This study opens up a vulnerable point in cancer and confirms that dietary therapy can be combined with existing cancer therapies to precisely eliminate tumors.

The study revealed an unexpected role of fatty acids. During fasting or a ketogenic diet, the levels of free long-chain fatty acids increase, acting as signaling molecules that activate the nutrient sensor AMPK (adenosine monophosphate-activated protein kinase). AMPK further enhances the phosphorylation of MNK (MAPK-interacting kinase), which belongs to the kinases that phosphorylate eIF4E.

At this point, a complete fatty acid-mediated signaling pathway becomes clear—the AMPK-MNK-eIF4E axis regulates the ketogenic process and links ketogenesis to translational control.

After identifying this signaling pathway, Professor Ruggero realized the fascinating connection between these findings and cancer treatment. Previously, Professor Ruggero and his collaborators developed a cancer candidate drug, tomivosertib (eFT508). This drug molecule, still in clinical trials, acts as an MNK1 and MNK2 inhibitor. Scientists have tried using eFT508 to treat pancreatic cancer by blocking eIF4E production to curb tumor growth. However, since glucose and carbohydrates can maintain energy supply, pancreatic cancer can continue to develop.

Given this, could changing dietary strategies and adopting a ketogenic diet, which uses fat for energy, block cancer cells' energy supply and enhance the therapeutic effect of eFT508?

In the latest study, Ruggero's team conducted experiments on mice. The research team first put the mice on a ketogenic diet, forcing pancreatic tumors to consume only fat, and then administered the cancer drug eFT508. In this condition, the drug cut off the only nutrient supply to the cancer cells, and the tumors shrunk.

In previous clinical trials, the safety of eFT508 in humans has been confirmed. The latest research shows that the combined use of eFT508 and a ketogenic diet can precisely eliminate pancreatic cancer.

Thus, this study reveals a new vulnerability in pancreatic cancer and finds that inhibitors of eIF4E phosphorylation can target this vulnerability, providing a theoretical basis for the combined therapy of dietary intervention and small molecule drugs. The research team also speculated that, beyond pancreatic cancer, most other cancers also have their respective vulnerabilities, so there is hope for finding more precision cancer treatment plans incorporating dietary strategies in the future.