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

靶向聚（ADP 核糖）聚合酶（PARP）治疗子宫内膜癌

• 批准号: 10533380
• 负责人: Saravut Weroha
• 金额: $ 18.21万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533380
• 关键词: Aftercare; Allelic Imbalance; Animals; BARD1 gene; Biological Assay; Cancer Patient; Carcinoma; Carcinosarcoma; Chemoresistance; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; DNA Double Strand Break; DNA Repair; DNA Repair Disorder; Data; Dependence; Development; Diagnosis; Dose; Drug Kinetics; ERBB2 gene; Endometrial Carcinoma; Exhibits; Exposure to; FDA approved; Formulation; Frequencies; Future; Genes; Genetic; Genomics; Histologic; Histology; Investigation; Label; Loss of Heterozygosity; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mesenchymal; Messenger RNA; Methods; Microsatellite Instability; Modality; Molecular; Mus; Mutation; Operative Surgical Procedures; Outcome; PARP inhibition; Patients; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Preclinical Drug Development; Progression-Free Survivals; RAD51C gene; Recurrence; Recurrent disease; Resistance; Role; Serous; Somatic Mutation; Specimen; System; Testing; Time; Topoisomerase; Trastuzumab; Tumor Volume; Validation; chemotherapy; cohort; design; efficacy evaluation; efficacy testing; functional disability; homologous recombination; improved; in vivo; in vivo Model; inhibitor; molecular subtypes; novel; novel therapeutics; patient derived xenograft model; patient stratification; pembrolizumab; phase I trial; phase II trial; predicting response; recombinational repair; response; screening; synergism; targeted treatment; three dimensional cell culture; transcriptome sequencing; transcriptomics; tumor

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.

项目概要/摘要 子宫内膜癌（EC）是最常见的妇科恶性肿瘤，患有子宫内膜癌的患者预后较差 浆液组织学。化疗耐药在复发性疾病中很常见，靶向治疗很少 可用。然而，越来越多的证据表明，一些浆液性或分子浆液性 EC 同源重组（HR）缺陷（HRD）的证据。在这里我们展示了 EC 患者衍生的 异种移植 (PDX) 模型还揭示了浆液性 EC 中 HRD 的频率较高，这是由基因组确定的 HRD 评分（基于端粒等位基因不平衡、大状态转变和杂合性丧失）。浆液性 EC 对 rucaparib（一种聚（ADP 核糖）聚合酶 (PARP) 抑制剂 (PARPi)）也更敏感。 vivo 3D培养系统。为了确认 HRD 高 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，事实上，观察到的协同作用 与 HR 修复缺陷一致。 HRD 的进一步验证在体内 PDX 中得到证实 研究表明，rucaparib 与新型 SN38 制剂 (PLX038A) 的组合产生了显着的效果 以及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， 需要调查几个问题以促进 PARPis 的临床使用和/或与 PLX038A。目前尚不清楚其他 EC（例如浆液样，无论组织学如何）的 HRD 评分是否会 预测对 PARPi 的反应，以及是否可以通过纳入另一个组学数据来改善遗传 HRD 评分 更准确地预测对 PARPi 的反应。检验 EC 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 缺陷，以下目标是 计划。我们建议 i) 使用基因组 HRD 评分和新型 mRNA 预测 PARPi 敏感性 PARPi 响应的特征，ii) 确定 rucaparib 单独使用以及与 SN38 联合使用的功效 更大的 EC PDX 离体和体内队列，以及 iii) 评估与 PARPi 相关的双组学评分 原发性患者肿瘤离体新鲜手术标本的反应。由此产生的数据 该申请将用于证明 PARPis 在分子定义的 EC 子集中的临床使用的合理性。此外， 由于 rucaparib + PLX038 目前正在进行 1 期试验 (NCT04209595)，并计划在 2019 年开展 2 期试验 卵巢癌，这些数据将支持 EC 的扩展队列。