Discovery of novel MDM2-targeted therapy for pediatric AML

Dr. Muxiang Zhou – Emory University, Atlanta, GA

AML is a hard-to-treat blood cancer of children. Currently, about 50-60% of children with AML do not respond well to treatment. In addition, chemotherapy often has severe, toxic side effects that can have long-term consequences for patient survival and quality of life. Thus, there is an urgent need to discover and develop more effective and less toxic drugs to improve the treatment for AML. The objectives of this project are to elucidate a novel pathway regulated by the interaction between two factors called tubulin and MDM2 for AML progression and to evaluate a novel tubulin inhibitor termed VERU-111 as a targeted agent for treatment of AML. This is clinically important, since MDM2 overexpression has been detected in over a third of patients with AML and is associated with exceptionally poor prognosis. We have found that VERU-111 binding to tubulins can strongly degrade MDM2, resulting in potent cell death of MDM2-overexpressing AML cells but not normal cells. Thus, we hypothesize that VERU-111 may be an effective targeted agent for precision treatment of AML patients with refractory/MDM2 overexpressing leukemic cells. We will test this possibility by performing preclinical studies, both in laboratory experiments and in animal models. Since VERU-111 is clinically available and currently in trials for treatment of another type of cancer, our ultimate goal will be to pursue expedited initiation of VERU-111 in an AML Phase-1 clinical trial.