Tuesday, December 3, 2024
12/3/2024
Project Summary Nearly all ovarian cancer deaths result from platinum-resistant high-grade serous tubo-ovarian carcinoma (HGSC), which typically responds poorly to PARP inhibitors, other “targeted therapies,” conventional chemotherapy, and/or immune checkpoint blockade. Approximately 20% of HGSC is driven by CCNE1 amplification (CCNE1amp), which almost always leads to platinum resistance. This MPI application joins experts in cancer biology/signal transduction/mouse modeling (NEEL) and HGSC genomics/therapeutics (LEVINE) with the overall objective of improving treatment of this poorly responsive subgroup. We contend that achieving this goal will require detailed analysis of sophisticated, genetically informed, immune-competent models of CCNE1amp HGSC. To this end, we developed a novel, mouse fallopian tube epithelial (FTE) organoid platform that can be used for rapid modeling of combinations of the genetic defects seen in human HGSC, as well as organoid and patient-derived xenograft (PDX) models of normal FTE and human CCNE1amp HGSC. In work under review, we found that Brca1-deleted, Ccne1-overexpressing (Ccne1OE), and Pten/Nf1-deleted FTE organoids differ in proliferation/differentiation, cytokine/chemokine secretion, and drug response in vitro, and evoke tumors with distinct kinetics, transcriptomes, and tumor immune microenvironments (TMEs) upon orthotopic injection (ovarian bursa) into syngeneic mice. Based on this information, we devised a chemo- immunotherapy regimen that yields T cell-dependent, durable, apparently curative, complete responses (CR) in a highly aggressive Tp53-/-;Ccne1OE;Akt2OE;KrasOE HGSC model. We now propose to: (i) clarify the mechanistic of efficacy of this combination regimen, (b) determine the effects of other mutational events that co-occur frequently with CCNE1amp on the phenotype of Tp53-/-;Ccne1OE FTE in vitro and in vivo, including whether our combination regimen is broadly efficacious in Ccne1OE HGSC, and (c) assess the relevance of these findings in human organoid and PDX models of CCNE1amp HGSC.
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