Targeting poly (ADP ribose) polymerase (PARP) in endometrial cancer

项目摘要/摘要 子宫内膜癌(EC)是最常见的妇科恶性肿瘤，其预后较差。 浆液性组织学。化疗耐药在复发性疾病中很常见，很少有靶向治疗 都是可用的。然而，越来越多的证据表明，一些浆液性或分子浆液性内皮细胞 同源重组(HR)缺陷(HRD)的证据。在这里我们展示了EC患者派生的 异种移植(PDX)模型还显示，由基因组确定的浆液性EC中HRD的频率更高 HRD评分(基于端粒等位基因不平衡、大状态转换和杂合性丢失)。严肃的 EC对Rucaparib也更敏感，Rucaparib是一种多(ADP核糖)聚合酶(PARPI)抑制剂 活体3D培养系统。为了证实HRD-High EC对HR DNA修复的依赖性，使用SN38 与rucaparib同时引起单链和双链DNA断裂，实际上，观察到的协同作用 与HR修复缺陷相一致。HRD的进一步验证在体内PDX中得到了证实 研究表明，RUCAPRIB与SN38(PLX038A)的新配方相结合，导致了显著的 和无与伦比的肿瘤消退。值得注意的是，八只小鼠中有四只患有无法检测到的肿瘤。然而， 几个问题需要调查以促进PARPis的临床使用和/或与 PLX038A。目前尚不清楚其他EC(如浆液性，无论组织学如何)的HRD评分是否会 预测对PARPI的响应以及是否可以通过包括另一个组学数据来改善遗传HRD得分 更准确地预测对PARPI的反应。来检验ECS中的HRD分数可以预测的假设 对PARPI的反应以及与SN38的协同作用取决于HR不足，以下目标是 有计划的。我们建议：1)使用基因组HRD评分和一种新的mRNA来预测PARPI敏感性 PARPI反应的签名，II)确定鲁卡帕利单独和与SN38联合治疗的疗效 更大的EC PDX体外和体内队列，以及III)评估与PARPI相关的双重组学评分 新鲜手术标本对原发肿瘤的体外反应。由此产生的数据 应用将被用来证明PARPis在分子定义的ECs子集中的临床使用的合理性。此外, 由于Rucaparib PLX038目前处于第1阶段试验(NCT04209595)，计划在#年开始第2阶段试验 卵巢癌，这些数据将支持EC的扩展队列。

Project Summary/Abstract Endometrial cancer (EC) is the most common gynecologic malignancy with poor outcomes for those with serous histology. Chemotherapy resistance is common in recurrent disease and very few targeted therapies are available. However, there is growing evidence that some serous or molecularly serous-like ECs have evidence for homologous recombination (HR) deficiency (HRD). Here we show that EC patient derived xenograft (PDX) models also revealed a higher frequency of HRD in serous EC, as determined by a genomic score of HRD (based on telomeric allelic imbalance, large state transitions, and loss of heterozygosity). Serous EC were also more sensitive to rucaparib, a poly (ADP ribose) polymerase (PARP) inhibitor (PARPi), in an ex vivo 3D culture system. To confirm the dependence of an HRD-high EC on HR DNA repair, SN38 was used to provoke single- and double-strand DNA breaks concurrently with rucaparib and indeed, the observed synergy was consistent with a deficiency of HR repair. Further validation of HRD was demonstrated in an in vivo PDX study showing the combination of rucaparib plus a novel formulation of SN38 (PLX038A) resulted in a marked and unparalleled regression of tumors. Remarkably, four of eight mice had undetectable tumors. However, several questions require investigation to facilitate the clinical use of PARPis and/or the combination with PLX038A. It is unknown whether the HRD score of other ECs (e.g serous-like, regardless of histology) will predict response to a PARPi and if the genetic HRD score can be improved by including another omics data to more accurately predict response to a PARPi. To test the hypothesis that an HRD score in ECs can predict response to a PARPi and the synergy with SN38 is dependent on HR deficiency, the following aims are planned. We propose to i) predict PARPi sensitivity using the genomic HRD score and a novel mRNA signature of PARPi response, ii) determine the efficacy of rucaparib alone and in combination with SN38 in a larger cohort of EC PDXs ex vivo and in vivo, and iii) evaluate a dual-omics score in relation to PARPi response in fresh surgical specimens of primary patient tumors ex vivo. The data generated from this application will be used to justify clinical use of PARPis in a molecularly defined subset of ECs. In addition, since rucaparib + PLX038 is currently in phase 1 trials (NCT04209595) with plans to open a phase 2 trial in ovarian cancer, these data will support an expansion cohort in EC.