DESCRIPTION (provided by applicant): This renewal application of the Mayo SPORE in Ovarian Cancer (OvCa) builds on translational OvCa research performed during Years 1-5 of funding. Our accomplishments include i) new understanding of the action of PARP inhibitors (PARPis), oncolytic measles virus, and immune suppressive cells in OvCa, ii) identification of 11 new risk loci for OvCa, iii) enrollment of 238 patients (pts) on SPORE therapeutic trials, iv) distribution of over 10,000 biospecimens for OvCa research, v) creation of 243 unique patient-derived OvCa xenografts and vi) publication of 136 articles. The Developmental Research Program (DRP) has contributed to 3 of the 4 projects in this renewal; and the Career Development Program (CDP) provided co-Leaders of two of the projects. The overall goal of the SPORE remains to support innovative, interactive, translational OvCa research that leverages the expertise of basic and translational investigators at Mayo Clinic and collaborating institutions. This renewal contains four translational projects designed to investigate OvCa biology and therapeutic response: * P1 (Novel determinants of PARPi sensitivity in OvCa) addresses the FDA call for better identification of OvCa pts most likely to respond to PARPis. PARPi resistance will be studied in homologous recombinationdeficient OvCa models and in samples from the only large multi-institution phase II PARPi trial in OvCa that requires pretreatment biopsies prior to single-agent PARPi treatment. * P6 (Targeting Protein Kinase C??[PKC?] for OvCa therapy) focuses on the only oncogenic kinase consistentlyamplified in high-grade serous OvCa. The role of PKC??in OvCa proliferation and drug resistance will beexamined in preclinical models; and the effect of inhibiting PKC??in clinical OvCa will be assessed in the OvCa expansion cohort of a phase 1 trial of TEV44229, the first specific PKC??inhibitor to be tested clinically. * P7 (Metformin as a metabolic therapeutic in OvCa) assesses the mechanistic basis for our observation that metformin, an agent administered for diabetes and nondiabetic conditions for over 20 years, enhances survival of diabetic OvCa pts. The accompanying randomized clinical trial is the first to prospectively examine the impact of adding metformin to standard therapy for OvCa in the first line setting. * P8 (A Th17-inducing dendritic cell vaccine for OvCa). Based on our observation that folate receptor? (FR?) is a frequent target of T cell immunity in OvCa and our clinical study showing that FR? peptides elicit a FR? CD4 T cell response that spreads to other OvCa antigens, P8 will assess for the first time the safety and immunological effects of dendritic cells pulsed with FR? peptides and matured to a Th17-inducing phenotype. These translational projects are supported by four highly interactive cores: Core A (Administrative), Core B (Biospecimens and Patient Registry), Core C (Biostatistics) and Core D (Animal Models). A DRP and CDP will be used to foster the next generation of translational OvCa investigators. Collectively, these SPORE activities will provide new insight into the biology of OvCa while advancing novel treatments for this lethal disease.
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