Wednesday, May 8, 2024
5/8/2024
Project Summary/Abstract Acute myeloid leukemia (AML) continues to have a dismal 5-year survival rate of <25% with chemotherapy. In addition, those who survive suffer lifelong consequences, due to complications from chemotherapy using non- targeted cytotoxic drugs such as cytarabine and anthracycline. Thus, there is an urgent need to discover and develop novel and targeted drugs that are more effective and less toxic to improve the treatment for AML. Studies have found that the human MDM2 oncogene is frequently overexpressed in AML, and high levels of MDM2 expression is associated with disease progression and poor treatment outcome. It is known that one of the oncogenic functions of MDM2 is to bind to the tumor suppressor p53, which inhibits p53-mediated transactivation in the nucleus leading to cancer promotion. MDM2 also plays p53-independent roles in oncogenesis by interacting with and regulating other molecules. For instance, MDM2 interacts with and regulates a/ß tubulins in the cytoplasm, which may play a p53-independent role in oncogenesis. This notion is derived from our observations that a novel tubulin inhibitor termed VERU-111 can specifically and strongly inhibit MDM2 expression without associated activation of p53. Significantly, we have found that AML-cell death induced by VERU-111 is correlated with the expression level of MDM2 in AML cells: leukemic cells with high-levels of MDM2 expression are very sensitive to VERU-111 with a IC50 value of 2.5~5 nM, whereas MDM2-negative AML cells are resistant, regardless of their p53 status (wild type or mutant p53). Based on these observations, we hypothesize that an important p53-independent oncogenic role of MDM2 is regulation of the microtubule network through its interaction with tubulins, leading to altered microtubule dynamics and carcinogenesis. We further hypothesize that VERU-111 blocks MDM2-tubulin interaction by binding to the colchicine site within the a/ß tubulin interface, leading to downregulation of MDM2 via increased ubiquitination and cancer cell death. The goal of this proposal is to use VERU-111 as a probe and AML as cell model to test our hypothesis and perform preclinical studies to validate that targeting the MDM2-microtubule signaling pathway by VERU-111 is a novel and attractive therapeutic strategy in MDM2-expressing AML. Specifically, we will elucidate the p53-independent role of MDM2 in interacting with and regulating a/ß tubulins for AML cell growth and disease progression (Aim 1). We will determine whether the MDM2-a/ß tubulin interaction is a target of VERU-111 (Aim 2). Additionally, we will investigate the feasibility of targeting the MDM2-a/ß tubulin signaling pathway by VERU-111 for precision and personalized treatment of refractory/MDM2-overexpressing AML (Aim 3). Since VERU-111 is well developed with oral availability, excellent PK properties and minimal toxicity; it has also passed extensive IND-enabling studies and is currently as a tubulin inhibitor in Phase 3 clinical trials for metastatic prostate cancer, knowledge generated from the proposed study should have near-term clinical impact by providing a rationale for expedited initiation of VERU-111 in an AML Phase-1 clinical trial.
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