Identification of a targeted anti-mitotic agent that degrades Myc and specifically induces cancer cell death

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PROJECT SUMMARY Ovarian cancer is the fifth leading cause of cancer death in women and chemotherapy has remained the standard of care for decades. Although 70% of high grade serous ovarian cancer (HGSOC) patients initially respond to platinum-based therapy, nearly all patients succumb due to lack of therapies to treat recurrent, chemotherapy-resistant disease. Therefore, there is an urgent need to identify targetable vulnerabilities of HGSOC and to develop new treatments to prolong survival of these patients. To address this problem, our lab used a computational drug repositioning platform, Drug Predict, to identify amiodarone, an antiarrhythmic agent, as a potential ovarian cancer treatment. Amiodarone potently decreased cell viability and triggered apoptosis in numerous patient-derived HGSOC cell lines, including those that were cisplatin-resistant. These effects were mediated through its ability to degrade c-Myc, which is overexpressed in >45% of HGSOC patients. However, given the dose-limiting toxicity of amiodarone, we applied structure-activity relationship analysis to identify DL78, which lacked hERG activity but retained the anti-cancer properties and ability to regulate Myc. DL78 was significantly more potent and tumor specific than amiodarone, and sensitized cells to platinum therapy. In addition, DL78 rapidly induced G2/M arrest and mitotic catastrophe, which ultimately led to apoptosis in several types of cancer cells. Furthermore, though both amiodarone and DL78 affected degradation of Myc, DL78 enhanced Myc phosphorylation on Threonine-58, consequently increasing proteasome-mediated Myc degradation. Thus, we hypothesize that DL78 induces mitotic catastrophe through Myc degradation and prolonged spindle assembly checkpoint (SAC) activation. We will test this hypothesis through two aims: 1) Examine DL78 effects on SAC activity and determine its dependency on Myc. 2) Investigate the compound’s in vivo efficacy in well-defined patient-derived xenografts. Successful completion of this proposal will improve our understanding of what molecular processes are vital to ovarian cancer cells’ survival. As a secondary outcome, it provides a compound that can be further developed into a preclinical candidate for ovarian & other Myc-driven cancers. The encouraging training environment, plentiful core facilities, and diverse mentorship presented to me at the University of Michigan will facilitate prosperous completion of these aims and bolster my professional development as a translational cancer researcher.