Joan & Sanford I. Weill Medical College of Cornell University
Project Term: December 31, 2019 - December 30, 2021
Our goal is to develop curative therapeutic regimens for the most aggressive forms of B-cell lymphoma, without unacceptable toxicity and in a manner that is widely applicable to patients regardless of access to the highest complexity health care. We propose that SIRT3 targeted therapy is important step to achieve this goal. Our preliminary data show that i) DLBCLs are broadly dependent on SIRT3 to maintain their survival regardless of genetic backgrounds and subtype, ii) SIRT3 expression is linked to inferior clinical outcome in DLBCL patients, iii) SIRT3 is required for lymphomagenesis in vivo, yet dispensable for normal B-cells. Mechanistically we showed that SIRT3 is the master regulator of anaplerotic metabolism in DLBCL, required to drive production of metabolic precursors through the TCA cycle to support the massive biosynthetic needs of lymphoma cells. Loss of SIRT3 function causes a precipitous drop in production of metabolic precursors in DLBCL cells, forcing them to engage in destructive autophagy which in turn triggers apoptosis.