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

项目概要/摘要 子宫内膜癌（EC）是最常见的妇科恶性肿瘤， 浆液性组织学化疗耐药常见于复发性疾病，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样EC具有 同源重组（HR）缺陷（HRD）。在这里，我们表明，EC患者来源于 异种移植（PDX）模型也揭示了浆液性EC中HRD的较高频率，如通过基因组学测定的那样。 HRD评分（基于端粒等位基因不平衡、大的状态转换和杂合性丢失）。浆液性 EC对rucaparib（一种聚ADP核糖聚合酶（PARP）抑制剂（PARPi））也更敏感， 体内三维培养系统。为了证实HRD-高EC对HR DNA修复的依赖性，使用SN 38来 与rucaparib同时引起单链和双链DNA断裂， 符合心率修复缺陷在体内PDX中证实了HRD的进一步验证 研究显示rucaparib加SN 38的新制剂（PLX 038 A）的组合导致显著的 和无与伦比的肿瘤消退。值得注意的是，八只小鼠中有四只有无法检测到的肿瘤。然而，在这方面， 有几个问题需要研究，以促进PARPis和/或与 PLX038A。目前尚不清楚其他EC的HRD评分（例如浆液样，无论组织学如何）是否 预测对PARPi的反应，以及是否可以通过包括另一组学数据来改善遗传HRD评分， 更准确地预测对PARPi的反应。为了检验EC中的HRD评分可以预测 对PARPi的反应以及与SN 38的协同作用取决于HR缺乏，以下目标是 计划好了我们建议i）使用基因组HRD评分和新的mRNA预测PARPi敏感性， ii）确定单独的鲁卡帕尼和与SN 38组合的鲁卡帕尼在PARPi应答中的功效， 离体和体内EC PDX的较大群组，和iii）评估与PARPi相关的双组学评分 在原发性患者肿瘤的新鲜手术标本中的离体反应。由此产生的数据 申请将用于证明PARPis在分子定义的EC子集中的临床使用。此外，本发明还提供了一种方法， 由于rucaparib + PLX 038目前处于1期试验（NCT 04209595），计划在2015年开始2期试验， 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.