? Project 6 Ovarian cancer remains the deadliest gynecological cancer, underscoring the need for better treatment options. Our published work demonstrates that PKC?, a PKC isoform not targeted by PKC inhibitors previously tested in the clinic, is an oncogene in ovarian and non-small cell lung cancer (NSCLC), where it plays critical roles in tumor initiation and progression. PKC? is also genetically activated in the most common serous ovarian tumor subtype: ~80% of high grade serous ovarian tumors exhibit PRKCI copy number gains associated with elevated PKC? expression. Interestingly, our published and preliminary data demonstrate that PKC? drives tumorigenesis in the ovary by a distinct, novel mechanism not observed in other tumors. Specifically, our preliminary studies indicate that: 1) ovarian cancer cells are ?addicted? to PKC? such that genetic or pharmacologic inhibition of PKC? leads to loss of ovarian cell growth and viability; 2) PKC? maintains a chemoresistant phenotype in ovarian cancer cells characterized by stem-like behavior, enhanced resistance to cisplatin and enhanced tumorigenicity; 3) PKC? activates a novel oncogenic PKC?- SOX2-HIPPO/YAP1 signaling pathway in these chemoresistant tumor-initiating cells (TICs); and 4) a novel small molecule PKC? inhibitor developed in collaboration with a pharmaceutical partner inhibits proliferation and viability of both bulk tumor cells and chemoresistant TICs. Based on these data we hypothesize that: 1) PKC? maintains a chemoresistant phenotype, in part, through activation of HIPPO/YAP1 signaling; 2) a novel PKC? inhibitor will effectively inhibit this pathway and block ovarian cancer cell transformed growth; 3) high grade serous ovarian cancers harboring PRKCI amplification and PKC? overexpression are ?addicted? to PKC? and will, therefore, be more responsive to PKC? inhibition than tumors without this genetic characteristic; 4) components of oncogenic PKC?-SOX2- HIPPO/YAP1 signaling can be developed as pharmacodynamic biomarkers of PKC? inhibition and possible predictive biomarkers of ovarian cancer sensitivity to PKC? inhibitor therapy; 5) a highly potent and specific PKC? inhibitor will effectively inhibit tumor PKC? and exhibit anti-tumor activity in a first-in-human therapeutic trial. These hypotheses will be tested through completion of three interrelated specific aims to: 1) dissect the mechanism by which PKC? regulates chemoresistant ovarian cancer cell behavior and assess the effect of PKC? inhibition on these cells; 2) assess the effect of PKC? inhibitor on primary serous ovarian cancer growth and validate biomarkers of response to PKC? inhibition using well validated patient-derived xenograft models; and 3) assess the ability of a highly potent and specific PKC? inhibitor to inhibit PKC? clinically in a first-in-human phase I clinical trial. Collectively, these studies will provide the first rigorous test of the hypothesis that PKC? can be targeted for therapeutic benefit in ovarian cancer.
Protein Kinase C? is an oncogene that is overexpressed in the majority (~70-80%) of high grade serous ovarian cancers as a result of tumor-specific gene amplification. PKC? plays a critical role in the establishment and maintenance of a chemoresistant, tumor-initiating phenotype in ovarian cancer cells. This application proposes to identify the specific signaling pathways by which PKC? drives ovarian cancer cell growth, identify tumor biomarkers of PKC? signaling, and conduct a first-in-human phase I clinical trial of a novel PKC? inhibitor as a new approach to treating ovarian cancer.
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