Feasibility Study of Dual Inhibition of MDM2 and Tubulin in Treatment of AML
AML is a common blood cancer of children. Currently, about 30-40% of children with AML fail to 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, development of more effective, less toxic drugs for AML based on biomarker-targeted therapy is critical. Studies have found that a protein called MDM2 is frequently overexpressed in leukemic cells from AML patients, and high level of MDM2 (relative to normal cells, i.e. MDM2 overexpression) is associated with disease progression and poor treatment outcome. MDM2 has been well studied to inhibit the tumor suppressor gene called p53 for cancer progression. We have recently discovered a novel function of MDM2 in cancer progression through interacting with and regulating a group of proteins called tubulins. Tubulins together form microtubule that plays critical cellular functions including those implicated in cancer. Thus, tubulin is an attractive cancer drug target and several tubulin inhibitors have been developed and approved by FDA for cancer treatment. Interestingly, we found that a novel investigative tubulin inhibitor termed TMI-70 not only inhibits tubulins but also specifically and strongly degrades MDM2. Significantly, AML-cell death induced by TMI-70 is correlated with the expression level of MDM2: leukemic cells with high-levels of MDM2 expression are very sensitive to TMI-70, whereas MDM2-negative AML cells are resistant. Thus, we believe TMI-70 may be an effective dual MDM2 and tubulin-targeted agent for precision treatment of AML patients with refractory/MDM2-overexpressing leukemic cells.
Project Goal:
The goals of this project are to elucidate a novel pathway regulated by the interaction between two factors called MDM2 and tubulin for AML cell proliferation and chemoresistance and to evaluate a novel small molecule chemical compound termed TMI-70 as a dual inhibitor of MDM2 and tubulin for treatment of AML. Specifically, we will investigate how high levels of MDM2 interact with tubulin to increase AML cell growth and decrease sensitivity to chemotherapy. Additionally, we will evaluate the ability of TMI-70 to inhibit and induce death of AML cells with overexpression of MDM2. 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. In our preliminary studies, we have found that TMI-70 binds to tubulin, which can block the interaction between tubulin and MDM2, resulting in specific and strong MDM2 protein degradation; this leads to potent cell death of MDM2-overexpressing AML cells but not MDM2-negative AML cells and normal cells. Thus, we hypothesize that TMI-70 may be an effective/less toxic agent for precision treatment of AML patients with refractory/MDM2-overexpressing leukemic cells. Accordingly, we propose to define the mechanism by which TMI-70 inhibits MDM2 overexpression. We will also evaluate the ability of TMI-70 to inhibit growth and induce death of AML cells with MDM2 overexpression, both in laboratory cultures and in mice engrafted with human AML. Our ultimate goal will be to pursue clinical application of TMI-70 in treatment of refractory/MDM2-overexpressing AML.
