NCI-funded study to identify metabolic vulnerabilities of particularly aggressive cancers

Eileen White, PhD, associate director for basic science at The Cancer Institute of New Jersey and professor of molecular biology and biochemistry at Rutgers, The State University of New Jersey, and colleagues from Princeton University have been awarded a new five-year, $2.4 million dollar research grant (1R01CA 163591-01) from the National Cancer Institute. The funding will support research to identify metabolic vulnerabilities of particularly aggressive cancers - those with mutations in the Ras cancer gene. The Cancer Institute of New Jersey is a Center of Excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (RWJMS).

Led by principal investigators Dr. White and Joshua D. Rabinowitz, MD, PhD, professor in the Department of Chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton University, the project is an extension of a collaborative effort between their two laboratories. That work, which has examined cancer metabolism, was initially funded through a National Institutes of Health Challenge Grant.

For nearly half a century, it has been known that altered metabolism distinguishes cancer cells from normal cells. Only recently have scientists learned that activation of cancer genes and loss of tumor suppressor genes reprograms cell metabolism. With this altered metabolism, cancer cells acquire the ability to make building blocks for production of new cancer cells and produce the energy needed for cancer growth.

The current project aims to identify the 'Achilles heel' in the altered metabolism of cancer cells that are specifically fueled by mutations in the Ras gene. Cancer-causing mutations in Ras proteins activate Ras signaling that promotes cancer cell growth. Ras mutations cause the most deadly cancers such as pancreatic, lung and colon cancers. Targeting Ras proteins directly with intended therapeutics has been unsuccessful, thus prompting investigators to instead look at blocking the downstream consequences of Ras function. But in order to do that, they must first identify what Ras needs to convert normal cells into tumor cells, including how Ras alters metabolism in ways that are essential for tumor growth.

The White and Rabinowitz laboratories recently examined Ras activation and its impact on tumor cells. They found that Ras-driven cancers are dependent on a self-preservation process known as autophagy, in which cells cannibalize themselves in order to survive stressful conditions during tumor growth and in response to therapy. In this project, White and Rabinowitz aim to further explore metabolic dependence and autophagy addiction as metabolic vulnerabilities that can be exploited in the development of new cancer therapies.

White, who also is the program leader of the Cell Death and Survival Signaling Program at The Cancer Institute of New Jersey and an adjunct professor of surgery at RWJMS, notes, "We have already shown that Ras-driven cancers are vulnerable to interference in specific metabolic pathways. By further examining these metabolic liabilities, we will be able to identify additional weaknesses that can be targeted therapeutically to provide new treatments for Ras-driven cancers."