PICTURE: Wistar scientists characterized an inhibitor that targets acetate metabolism in cancer cells. This molecule caused inhibition and regression of tumor growth in preclinical studies and demonstrated the promise of this approach as a … view More
Photo credit: The Wistar Institute
PHILADELPHIA – (Jan. 7, 2021) – Scientists at the Wistar Institute characterized an inhibitor that targets acetate metabolism in cancer cells. Cancer cells use acetate metabolism to support tumor growth when there is little nutrient and oxygen availability. This molecule caused inhibition and regression of tumor growth in preclinical studies and showed the promise of this approach as a novel therapeutic strategy for solid tumors. The study results were published today in Cancer Research, a journal of the American Association for Cancer Research.
With strongly proliferating cancer cells within a tumor, there is often a severe lack of oxygen and nutrients. To meet their high metabolic needs for energy production and synthesis of macromolecules, cancer cells adapt over time and evolve to survive and continue to grow on various sources of nutrients. The changes that come with this rewiring of metabolism represent a critical barrier to cancer treatment.
The laboratory of Zachary T. Schug, Ph.D., Assistant Professor in the Molecular and Cellular Oncogenesis Program at the Wistar Institute’s Cancer Center, examines the metabolic changes that occur during tumor progression to identify targets that will be used in new effective cancer treatments can .
In particular, they focus on the role of acetate metabolism. She and others have identified acetate as an important alternative source of nutrients for cancer cells, and established that the ACSS2 enzyme, which converts acetate to acetyl-CoA, is critical for tumor growth under nutrient-stressed conditions. Acetyl-CoA is an essential metabolite used by cancer cells for many basic cellular processes and for energy production.
“We wanted to test whether the pharmacological inhibition of ACSS2 could prevent tumor growth and offer a significant therapeutic opportunity for cancers that are fueled by acetate,” said Schug, who is lead author of the study.
Working with Joseph Salvino, Ph.D., professor at the Wistar Institute’s Cancer Center and an expert in medicinal chemistry, Schug and colleagues synthesized and tested an inhibitor of the ACSS2 enzyme and showed that this molecule, called VY-3-135, is effective and highly specific in blocking the function of ACSS2 in breast cancer cell lines. It is important that treatment with VY-3-135 inhibited acetate metabolism in tumors in vivo and markedly inhibited tumor growth in preclinical breast cancer models with high ACSS2 levels.
“Several studies have now shown that ACSS2 is essential in a variety of cancers, suggesting that acetate metabolism plays a near universal role in cancer and supports the promise of ACSS2 inhibitors for cancer treatment,” said Katelyn D. Miller, Ph.D. , Postdoctoral fellow in the Schug laboratory and lead author of the study.
“We look forward to advancing our studies and developing safe, potent ACSS2 inhibitors for clinical transmission,” added Schug.
Co-authors: Katherine Pniewski, Caroline E. Perry, Sara Papp, Joshua D. Shaffer, Jessica C. Casciano, Tomas M. Aramburu, Yellamelli VV Srikanth, Joel Cassel, Emmanuel Skordalakes, Andrew V. Kossenkov and Joseph M. Salvino von Wistar; Jesse N. Velasco-Silva from the University of Utah.
Work sponsored by: National Institutes of Health Grants New Innovator Award from NIH Director DP2 CA249950-01 and T32 CA009171; Grants from the WW Smith Charitable Trust, Susan G. Komen®, and the V Foundation for Cancer Research. Assistance for the Wistar Institute facilities was provided by Cancer Center Support Grant P30 CA010815. The Wistar Proteomic and Metabolomic Facility is supported in part by NIH grants R50 CA221838 24 and S10 OD023586.
Publication Information: Targeting ACSS2 with a Transitional State Mimic Inhibits Triple Negative Growth in Breast Cancer, Cancer Research (2021). Online publication.
The Wistar Institute is an international leader in biomedical research with particular expertise in cancer research and vaccine development. Founded in 1892 as the first independent, not-for-profit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center award from the National Cancer Institute since 1972. The institute actively works to ensure that the progress of research gets from the laboratory to the clinic as quickly as possible. wistar.org.
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