Research Summary: High-grade serous ovarian cancer (HGSOC) is the most common histologic subtype of ovarian cancer. Despite ongoing efforts to develop effective surgical and treatment regimens for advanced HGSOC, the overall survival rate is only 30%, in part due to late diagnosis. HGSOC is among the most chemo-sensitive of all epithelial malignancies at diagnosis. However, a subset of advanced stage patients fails to respond to initial therapy and has a dismal prognosis. Therefore, understanding the mechanisms through which HGSOC metastasizes, and develops intrinsic chemoresistance is crucial to improve the efficacy of treatments and survival of patients. The proposed Ovarian Cancer Atlas Research Center (OCARC) will use and integrate multiple state-of-the-art molecular and cellular profiling platforms to construct a three-dimensional (3D) ovarian cancer atlas characterizing HGSOC metastasis, and the development of intrinsic therapeutic resistance using a diverse patient cohort diagnosed with advanced HGSOC. The Center is composed of an Administrative Core and three connected units: a Biospecimen Unit, a Characterization Unit, and a Data Processing Unit. The multi-PI team from MD Anderson Cancer Center, and the University of Arkansas, brings together internationally recognized experts in ovarian cancer biology and treatment, mass spectrometry, bioinformatics, and imaging. This team will have the complementary multidisciplinary scientific expertise required for the integration of the multidimensional, multiparametric data needed to construct a 3D ovarian cancer atlas and address the key research problems proposed. The Administrative Core will provide the support necessary for the proposed OCARC infrastructure. The Biospecimen Unit will acquire specimens, collect clinicopathologic information, and prepare tissue sections. The Characterization Unit will perform spatially resolved subcellular transcriptome profiling on FFPE tissue sections using the novel STOmics platform; 3D metabolomic and peptidomic and glycomic profiling using high-resolution mass spectrometry imaging; and 3D stromal and tumor cell profiling using the COMET multiplex immunofluorecence platform. The Data Processing Unit will build a data warehouse hosting all the data generated by the Characterization Unit and the Biospecimen Unit. It will be responsible for integrating all available data to identify the key signaling circuits that underlie the 3D spatial changes of phenotypic profiles. The final atlas will identify differences in the cellular and molecular content, and cell-cell crosstalk signaling networks in HGSOCs from (1) primary and metastatic sites; and (2) intrinsic chemosensitive and chemoresistant HGSOCs. It will bring deeper insight into the multidimensional HGSOC tumor ecosystems associated with intrinsic chemoresistance. We expect that our results will be used by academic researchers, clinical researchers, and industry partners to improve our understanding of the molecular basis of ovarian cancer and better stratify disease management and improve patient outcome. Our results will have the potential to lead to the development of novel agents against chemoresistant HGSOC.

Project Narrative The proposed study seeks to use multiple state-of-the–art molecular and cellular profiling platforms to construct a three-dimensional spatially resolved Ovarian Cancer Atlas using treatment naïve formalin fixed paraffin embedded (FFPE) ovarian tumor tissue samples obtained from the primary ovarian site and metastatic sites in racially diverse patients who are diagnosed with chemo-refractory or chemo-sensitive advanced high- grade serous ovarian cancer (HGSOC). We expect that the results will be used by academic researchers, clinical researchers and industry partners to improve our understanding of the molecular basis of the disease and better strategize disease management of patients. In addition, the results of this study would have the potential leading to the development of clinical trials testing novel agents against new molecular targets.