Michael Deininger, Ph.D., M.D. & Thomas O’Hare, Ph.D.

Acute myeloid leukemia (AML) has the most dismal prognosis of all blood cancers, and >70% of AML
patients will succumb to their disease. Therapy is still based on a chemotherapy regimen developed more
than three decades ago and what little progress has been made is attributable to improvements in
supportive care. Although most patients initially respond to therapy, leukemia stem cells survive in
sanctuary sites of the bone marrow and eventually cause relapse and death. Intense research has identified the major DNA mutations in AML, but this knowledge has not led to therapeutic breakthroughs. To overcome this stalemate, our translational medicine research team has taken a function-first approach to identify vulnerabilities in AML cells that are independent of genetic mutations and continue despite protection afforded by the bone marrow. We discovered that cells from most AML patients are highly dependent on SIRT5, an enzyme that regulates energy metabolism, while normal controls are not dependent on SIRT5. As no clinical SIRT5 inhibitors exist, these results prompted us to conduct a search for new SIRT5 inhibitors. We identified a highly promising candidate (HCI-0250) as the starting point for the development of a clinical SIRT5 inhibitor. We will validate SIRT5 as a therapy target in AML using mouse models reflecting key aspects of the clinical disease. In parallel, we will develop a potent and selective SIRT5 inhibitor as a candidate for clinical trials in AML. If successful, our work may lead to a new treatment paradigm applicable to a majority of AML patients.