Celgene Goes After Cancer’s Achilles’ Heel

The drug industry seems to be coming back around to the idea that cancer has an Achilles’ heel. In the latest deal related to cancer metabolism, Celgene is handing over $130 million upfront for access to oncology drugs coming out of Agios Pharmaceuticals‘ labs. Under the pact, Celgene, for a period of time, can opt-in on any drug candidate generated by Agios’ cell metabolism technology. Celgene can also put up extra cash to extend the opt-in period on a candidate.

Agios is focused on depriving cancer cells of their energy source by using small molecules to control critical metabolic enzymes. Those targets include isocitrate dehydrogenase (IDH1), shown to play a role in cancer formation, and pyruvate kinase M2 (PKM2), an enzyme involved in glucose metabolism. Carmen weighed in on their research in a piece on cancer metabolism back in February:

Agios researchers are looking at several metabolic enzyme targets. For example, they have found a surprising effect for brain-cancer-associated mutations in the enzyme isocitrate dehydrogenase 1. Rather than halting the enzyme’s dehydrogenase activity, the mutations cause it to catalyze a reduction, the researchers find (Nature 2009, 462, 739). The product of that reduction, a metabolite called 2-hydroxyglutarate, is over 100 times more abundant in tumors with the cancer-associated mutation. So the compound could be a useful marker in tests of a patient’s blood, urine, or cerebrospinal fluid to determine whether their tumor has the mutation. It could even be an indicator of whether certain experimental cancer drugs are working, says Joshua D. Rabinowitz, a coauthor of the work and consultant for Agios who studies metabolism at Princeton University.

The idea of targeting cancer metabolism isn’t new. As Carmen’s article notes, German biochemist Otto Heinrich Warburg first noticed a metabolic quirk in cancer cells—they break down glucose via an oxygen-free metabolic pathway, regardless of whether oxygen is available—in the 1920s.

There has been a revival of interest in the idea as researchers begin to understand the limitations of targeted therapies, molecules that often block a single protein kinase and, while effective in treating cancer for awhile, eventually stop working as resistance develops. In an editorial in the New York Times last August, James D. Watson, the granddaddy of DNA, advocated revisiting the concept of commonalities in cancer cells, specifically, how they metabolize glucose.

Now, interest is moving out of academic labs and into drug firms. In addition to the Celgene/Agios deal, AstraZeneca and Cancer Research UK are in a three-year research pact related to cancer metabolism. And the technology behind GSK’s questionable $720 million of Sirtris Pharmaceuticals is centered on depriving cells of energy.

Will any of this research pan out? Could there be a way to get to the very root of cancer?

Author: Lisa Jarvis

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