Microtubule stabilizing agents (MSAs) are some of the most widely used and effective therapies availablefor the treatment of solid tumors. However, their utility is compromised by innate and acquired drugresistance. The taccalonolides (taccas) are a mechanistically unique class of MSAs that circumventmultiple clinically relevant forms of drug resistance. Multiple potent taccas identified by our laboratorieshave effective antitumor activity in drug sensitive and resistant in vivo models but suffer from a narrowtherapeutic window.

We respond to PQ3 with our data showing that tumor PD-L1 (CD274, B7-H1) is a major regulator of tumorinflammatory infiltrates. Our preliminary data show that melanoma PD-L1 regulates TIL through severalpreviously unknown tumor-intrinsic and extrinsic mechanisms. We define novel effects of tumor intrinsic PD-L1signaling on tumor proliferation, sensitivity to immune killing, in vivo growth independent of anti-tumorimmunity, and regulation of mTOR signals.

Self-renewing tumor-propagating cells drive continued tumor growth and are responsible for relapse. If the processby which tumor cells self-renew could be turned off, then tumors would regress and patients would remain relapsefree. The goal of this updated proposal is to define the cellular and molecular mechanisms by whichNotch regulates tumor-propagating potential and plasticity of the tumor propagating cell state inembryonal rhadomyosarcoma (ERMS), a devastating pediatric malignancy of the muscle.

This exploratory project is directed towards understanding the biological role of a novel oncogenic driver inEwing sarcoma. Ewing sarcoma is an aggressive cancer of bone and soft tissues in children with poor long-term outcome. It is characterized by the chromosomal translocation generating a fusion oncogene betweenEWS and an Ets family transcription factor, most commonly FLI-1. EWS-FLI-1 translocation accounts for 85%of Ewing sarcoma cases.