New Approaches to Modeling and Targeting Cyclin E-amplified High-Grade Serous Tubo-Ovarian Carcinoma

项目摘要 几乎所有卵巢癌死亡都是由铂耐药的高级别浆液性输卵管卵巢癌引起的。 (HGSC)，通常对PARP抑制剂，其他“靶向治疗”，常规 化疗和/或免疫检查站封锁。大约20%的HGSC是由CCNE1驱动的 放大(CCNE1amp)，这几乎总是导致铂电阻。这款MPI应用程序加入了专家 癌症生物学/信号转导/小鼠建模(NEEL)和HGSC基因组学/治疗学(Levine) 总体目标是改善对这一反应不良亚群的治疗。我们认为，实现 这一目标将需要详细分析复杂的、遗传信息丰富的、具有免疫能力的模型。 CCNE1amp HGSC。为此，我们开发了一种新型的小鼠输卵管上皮(FTE)类器官平台 可用于快速建模人类HGSC中所见的遗传缺陷组合，以及 器官移植和患者来源的异种移植(PDX)模型的正常FTE和人CCNE1amp HGSC。在工作中 在审查中，我们发现BRCA1-缺失、Ccne1-过度表达(Ccne1OE)和Pten/Nf1-缺失FTE 在体外，有机化合物在增殖/分化、细胞因子/趋化因子分泌和药物反应方面存在差异 以不同的动力学、转录本和肿瘤免疫微环境(TME)诱发肿瘤 同基因小鼠原位注射(卵巢囊)。基于这个信息，我们设计了一种化疗- 免疫治疗方案，产生T细胞依赖的、持久的、明显治愈的完全应答(CR) 高度积极的TP53-/-；Ccne1OE；Akt2OE；KrasOE HGSC模型。我们现在建议：(I)澄清机制 (B)确定同时发生的其他突变事件的影响 CCNE1amp在体外和体内对TP53-/-；Ccne1OE FTE表型的影响，包括我们的 联合方案在治疗慢性HGSC方面大体有效，并且(C)评估这些发现在 CCNE1amp HGSC的人器官模型和PDX模型

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.