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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要子宫内膜癌（EC）是最常见的妇科恶性肿瘤，对于患有浆液组织学。化学疗法耐药性在复发性疾病中很常见，很少有靶向疗法可用。但是，越来越多的证据表明，某些浆液或分子状的EC具有同源重组（HR）缺陷（HRD）的证据。在这里，我们证明EC患者得出异种移植（PDX）模型还揭示了浆液EC中HRD较高的频率，如基因组确定 HRD的得分（基于端粒等位基因失衡，较大的状态过渡和杂合性丧失）。浆液 EC在EX Vivo 3D培养系统。为了确认HRD高EC对HR DNA修复的依赖性，SN38用于引发单链DNA与rucaparib同时断裂，实际上是观察到的协同作用与人力资源维修的不足一致。在体内PDX中证明了HRD的进一步验证研究表明rucaparib加上新型SN38（PLX038A）的组合导致了标记和无与伦比的肿瘤回归。值得注意的是，八只小鼠中有四只患有无法检测的肿瘤。然而，几个问题需要调查，以促进parpis和/或与/或与/或合并的临床使用。 PLX038A。尚不清楚其他EC的HRD评分（例如，无论组织学如何）是否会预测对PARPI的响应，以及是否可以通过将另一个OMIC数据包含到更准确地预测对PARPI的响应。为了测试以下假设，即EC中的HRD分数可以预测对PARPI和SN38协同作用的响应取决于人力资源缺乏症，以下目的是计划。我们建议i）使用基因组HRD评分和新的mRNA预测PARPI敏感性 parpi响应的签名，ii）确定单独的rucaparib的功效，并与sn38结合在a中较大的EC PDX的同类体体和体内，以及III）评估与PARPI有关的双摩学评分原发性肿瘤的新鲜手术标本反应。从中生成的数据应用将用于证明在EC的分子定义子集中PARPI的临床使用合理。此外，由于Rucaparib + PLX038目前正在1阶段试验（NCT04209595）中，并计划在卵巢癌，这些数据将支持EC的扩张队列。