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.
With 22,300 new cases and 15,500 deaths each year, epithelial cancer of the ovary, fallopian tube or peritoneum (ovarian cancer) remains the most lethal of the gynecological malignancies. The Mayo SPORE in Ovarian Cancer provides support for translational research projects that are designed to have a rapid impact on ovarian cancer patients through development and testing of four novel therapeutic approaches.
|Zhang, Qing; Wang, Chen; Cliby, William A (2018) Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer. Gynecol Oncol :|
|Morehead, Lauren C; Cannon, Martin J (2018) Further clinical advancement of dendritic cell vaccination against ovarian cancer. Ann Res Hosp 2:|
|Botuyan, Maria Victoria; Cui, Gaofeng; Drané, Pascal et al. (2018) Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. Nat Struct Mol Biol 25:591-600|
|Block, Matthew S; Vierkant, Robert A; Rambau, Peter F et al. (2018) MyD88 and TLR4 Expression in Epithelial Ovarian Cancer. Mayo Clin Proc 93:307-320|
|Earp, Madalene; Tyrer, Jonathan P; Winham, Stacey J et al. (2018) Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS One 13:e0197561|
|O'Mara, Tracy A; Glubb, Dylan M; Amant, Frederic et al. (2018) Identification of nine new susceptibility loci for endometrial cancer. Nat Commun 9:3166|
|Wu, Chenming; Luo, Kuntian; Zhao, Fei et al. (2018) USP20 positively regulates tumorigenesis and chemoresistance through ?-catenin stabilization. Cell Death Differ 25:1855-1869|
|Msaouel, Pavlos; Opyrchal, Mateusz; Dispenzieri, Angela et al. (2018) Clinical Trials with Oncolytic Measles Virus: Current Status and Future Prospects. Curr Cancer Drug Targets 18:177-187|
|Li, Lei; Liu, Tongzheng; Li, Yunhui et al. (2018) The deubiquitinase USP9X promotes tumor cell survival and confers chemoresistance through YAP1 stabilization. Oncogene 37:2422-2431|
|Lu, Yingchang; Beeghly-Fadiel, Alicia; Wu, Lang et al. (2018) A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk. Cancer Res 78:5419-5430|
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