Join us for an insightful “Ask the Author Session” welcoming Professor Gregory Steinberg, working at McMaster University, where he serves as a professor of medicine and director of the Center of Metabolism, Obesity and Diabetes. Professor Steinberg discusses his very interesting and really great paper published recently in Nature, titled “ACLY Inhibition Promotes Tumor Immunity and Suppresses Liver Cancer”.
In this session, Professor Steinberg explores the rationale for targeting the enzyme ATP citrate lyase (ACLY) to treat hepatocellular carcinoma (HCC), a rapidly rising cancer worldwide due to fatty-liver disease, or MASH (metabolic dysfunction-associated steatohepatitis). He explains that MASH-driven tumors are metabolically and immunologically different and often resist current immunotherapies.
Watch the Video to Discover the Breakthrough Connection Between Metabolism and Immune Activation!
The conversation delves into the fascinating preclinical work demonstrating that genetically removing ATP citrate lyase led to resolution of hepatocellular carcinoma in mice. ACLY is critical because it links fat and carbohydrate metabolism and is central to the synthesis of fat and cholesterol.
You will learn about the identification and development of a novel small-molecule ACLY inhibitor, EVT0185. This drug was found to be liver-selective through an activation mechanism, meaning it primarily targets the tumor in the liver, which is important for safety. Remarkably, the drug did not just slow tumor growth, but was actually killing the tumors, suggesting that the immune system was being engaged.
Professor Steinberg notes that this work is a first indication that affecting tumor metabolism has a huge impact on the immune system, reactivating it to find and kill tumors. The paper showed that ACLY inhibition enhances the effects of current standards of care, including immunotherapies and tyrosine kinase inhibitors. This mechanism involves linking reduced tumor ACLY with increases in the chemokine CXCL13, attracting B cells, and forming tertiary lymphoid structures (TLS). The depletion of B cells blocked the anti-tumor effects of ACLY inhibition.
Professor Steinberg shares that the drug is ready to move into Phase 1 clinical trials and expresses excitement for its potential future use as an adjuvant therapy after tumor resection to prevent patient relapse.
Don’t miss this opportunity to hear directly from Professor Steinberg about this beautiful paper in Nature.