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

项目摘要 几乎所有的卵巢癌死亡都是由铂类耐药的高级别浆液性输卵管卵巢癌引起的 （HGSC），其通常对PARP抑制剂反应差，其他“靶向治疗”，常规治疗， 化疗和/或免疫检查点阻断。大约20%的HGSC由CCNE 1驱动 放大（CCNE 1amp），这几乎总是导致铂电阻。此MPI应用程序加入了专家 癌症生物学/信号转导/小鼠模型（NEEL）和HGSC基因组学/治疗学（LEVINE） 其总体目标是改善该反应不良亚组的治疗。我们认为， 这一目标将需要对复杂的、遗传信息丰富的、具有免疫能力的模型进行详细分析， CCNE 1安培HGSC。为此，我们开发了一种新的小鼠输卵管上皮（FTE）类器官平台， 可用于快速建模在人类HGSC中观察到的遗传缺陷的组合，以及 正常FTE和人CCNE 1amp HGSC的类器官和患者来源的异种移植物（PDX）模型。在工作 在回顾中，我们发现Brca 1缺失、Ccne 1过表达（Ccne 1 OE）和Pten/Nf 1缺失的FTE 类器官在增殖/分化、细胞因子/趋化因子分泌和体外药物反应方面不同， 诱发具有不同动力学、转录组和肿瘤免疫微环境（TME）的肿瘤， 原位注射（卵巢囊）到同基因小鼠中。基于这些信息，我们设计了一种化疗- 免疫治疗方案产生T细胞依赖性的、持久的、明显治愈的完全应答（CR）， 高度侵袭性的Tp 53-/-; Ccne 1 OE; Akt 2 OE;KrasOE HGSC模型。我们现在建议：（一）澄清机制 （B）确定同时发生的其它突变事件的影响 CCNE 1amp在体外和体内对Tp 53-/-; CCNE 1 OE FTE表型的影响，包括我们是否 联合方案在Ccne 1 OE HGSC中广泛有效，并且（c）评估这些发现与Ccne 1 OE HGSC的相关性。 CCNE 1amp HGSC的人类器官和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.