SC COBRE in Oxidants, Redox Balance and Stress Signaling
James Chou, Ph.D.
James Chou, Ph.D.
Novel AML therapy targeting HDAC6 and Hsp90 Chaperone Complex
Acute myelogenous leukemia (AML) is one of the most common and aggressive forms of acute leukemia affecting 30,000 people per year. Survival greater than 5 years still remains around 10-30%, and this depends greatly on the patient’s ability to tolerate the combination of cytotoxic chemotherapies, which suppress much needed haemopoiesis. The limits of current treatment modalities indicate a need for innovative therapies directed against relevant biological targets in AML to improve the clinical outcome in AML. Heat-shock protein 90 (Hsp90) and histone deacetylase isozyme 6 (HDAC6) are required for the maintenance of AML oncogenic signaling and stability of oncogenic chimera transcription factors. Hsp90 and HDAC6 are constitutively over-expressed in AML patient blood mononucleocytes and bone marrows. HDAC6 is also required for malignant cell transformation both in transformed cells and in vivo. HDAC6/Hsp90 complex/chaperone activity requires active HDAC6, and inhibition of HDAC6 destabilizes Hsp90 complex and abolish its chaperone function. We have identified a novel class of selective HDAC6/Hsp90 inhibitors, which preferentially inhibit HDAC6 at low µM concentrations and rapidly induce inactive acetylated Hsp90 thereby resulting in Hsp90 client protein depletion. Our overarching hypothesis is that a functional HDAC6/Hsp90 complex is an essential part of AML pathogenesis. The proposal intends to use multifaceted and innovative approaches to develop novel HDAC6/Hsp90 complex inhibitors and to investigate the roles of HDAC6/Hsp90 complex in AML.