Genetic and genomic determinants of homologous recombination repair deficiency as treatment selection markers for lethal prostate cancer

同源重组修复缺陷的遗传和基因组决定因素作为致命性前列腺癌的治疗选择标记

• 批准号: 10531588
• 负责人: JUN LUO
• 金额: $ 36.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-03 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531588
• 关键词: Address; Alleles; Androgen Receptor; BRCA1 gene; BRCA2 gene; Biological Assay; Blood; Blood specimen; Cancer Patient; Categories; Cells; Clinical; Clinical Management; Clinical Trials; DNA sequencing; Data; Development; Diagnosis; Disease; Drug Targeting; Evaluation; Event; FDA approved; Gene Expression; Genes; Genetic; Genomics; Goals; Inherited; Knowledge; Lesion; Life; Link; Local Therapy; Longitudinal cohort; Malignant neoplasm of prostate; Molecular; Mutation; Operative Surgical Procedures; Patient Selection; Patients; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Prediction of Response to Therapy; Rationalization; Recurrence; Resistance; Resources; Role; Sampling; Selection for Treatments; Specimen; Systemic Therapy; Time; Tissues; Treatment outcome; Work; abiraterone; anticancer research; castration resistant prostate cancer; chemotherapy; cohort; docetaxel; enzalutamide; genetic predictors; genetic testing; genomic biomarker; homologous recombination; hormone therapy; improved; inhibitor therapy; liquid biopsy; men; molecular phenotype; mutational status; novel; patient oriented; patient population; predictive marker; prospective; recombinational repair; response; response biomarker; standard of care; targeted treatment; taxane; transcriptome sequencing; treatment comparison; treatment response; tumor; tumor DNA

PROJECT SUMMARY Homologous recombination (HR) deficiency (HRD), particularly from biallelic mutational loss of BRCA1/BRCA2/ATM (BRCA/ATM), is significantly enriched in men with metastatic castration-resistant prostate cancer (mCRPC). Such patients have multiple FDA-approved systemic life-prolonging therapies to choose from, including abiraterone, enzalutamide, and taxane chemotherapies, as well as the possibility of poly(ADP- ribose) polymerase (PARP) inhibitor therapy which currently remains investigational. A few recent studies suggest that patients with germline and/or somatic HRD mutations may respond better (and for longer durations of time) to novel hormonal therapies than their HRD-negative counterparts. These studies suggest that in addition to PARP inhibition, potent AR suppression is also “synthetic lethal” with HRD in mCRPC. However, the genetic/genomic determinants of HRD and their role in treatment selection remain unknown. We propose a resource-driven, patient-centered study to determine the genetic/genomic drivers of HRD predicting “deep” response to abiraterone and enzalutamide. We hypothesize that mCRPC patients can be categorized into three groups according to HRD status defined by deleterious mutations in HRD genes: 1) germline/somatic HRD; 2) somatic-only HRD; 3) negative HRD; and that these groups are molecularly distinct, and have different clinical implications as predictive markers of response to AR-targeting therapies and taxane chemotherapies. To address the overall hypothesis, it is necessary to establish clinical and tumor/normal specimen cohorts that enable detailed molecular and clinical characterization of HRD in men with mCRPC. In Specific Aim 1, we will seek to ascertain the HRD mutations status, both somatic and germline, in three existing advanced/lethal prostate cancer cohorts enriched for HRD using blood-based assays. In Specific Aim 2, we will determine the association of HRD status defined by blood-based assays with treatment response to first-line AR-directed therapy (abiraterone/enzalutamide) and taxane chemotherapies in mCRPC patients by comparing treatment outcomes of men in these three groups. In Specific Aim 3, we seek to determine the expression correlates of HRD status defined by blood-based assays and further ascertained by tissue-based assays, by performing RNA-Seq in surgical specimens from men with lethal prostate cancer with: 1) germline/somatic HRD; 2) somatic-only HRD; and 3) negative HRD. The proposed work addresses an unmet need due to focus on liquid biopsy markers in a vulnerable patient population facing difficult treatment decisions. Also, our effort in defining the clinical and functional implications of HRD status in established cohorts of mCRPC patients will directly lead to treatment selection strategies to improve clinical management as well as patient selection strategies for clinical trials.

项目概要 同源重组（HR）缺陷（HRD），特别是由于双等位基因突变丢失 BRCA1/BRCA2/ATM (BRCA/ATM) 在患有转移性去势抵抗性前列腺的男性中显着富集 癌症（mCRPC）。此类患者有多种 FDA 批准的系统性延长生命疗法可供选择 包括阿比特龙、恩杂鲁胺和紫杉烷化疗，以及聚（ADP- 核糖）聚合酶（PARP）抑制剂疗法目前仍在研究中。最近的一些研究 表明具有种系和/或体细胞 HRD 突变的患者可能会有更好的反应（并且持续时间更长） 与HRD阴性的同行相比，新的激素疗法的持续时间）。这些研究表明 除了 PARP 抑制之外，强效 AR 抑制对于 mCRPC 中的 HRD 也具有“综合致死性”。 然而，HRD 的遗传/基因组决定因素及其在治疗选择中的作用仍然未知。我们 提出一项资源驱动、以患者为中心的研究，以确定 HRD 预测的遗传/基因组驱动因素 对阿比特龙和恩杂鲁胺的“深度”反应。我们假设 mCRPC 患者可以分为 根据 HRD 基因有害突变定义的 HRD 状态分为三组：1) 种系/体细胞 人力资源开发； 2）纯躯体HRD； 3）HRD负值；并且这些基团在分子上是不同的，并且具有 作为 AR 靶向疗法和紫杉烷反应预测标志物的不同临床意义 化疗。为了解决总体假设，有必要建立临床和肿瘤/正常 样本队列能够对患有 mCRPC 的男性 HRD 进行详细的分子和临床表征。在 具体目标 1，我们将寻求确定 HRD 突变状态，包括体细胞和种系，三个 现有的晚期/致命性前列腺癌队列使用基于血液的检测方法丰富了 HRD。特定目标 2，我们将确定基于血液的检测定义的 HRD 状态与治疗反应的关联 mCRPC 患者的一线 AR 定向治疗（阿比特龙/恩杂鲁胺）和紫杉烷化疗 比较这三组男性的治疗结果。在具体目标 3 中，我们寻求确定 HRD 状态的表达与基于血液的检测确定并通过基于组织的检测进一步确定 通过对患有致命性前列腺癌的男性手术标本进行 RNA 测序来进行检测：1) 种系/体细胞HRD； 2）纯躯体HRD； 3) 负 HRD。拟议的工作解决了一个未满足的问题 需要关注面临困难治疗的弱势患者群体的液体活检标志物 决定。此外，我们在确定 HRD 状态的临床和功能影响方面所做的努力 mCRPC 患者队列将直接导致治疗选择策略以改善临床管理 以及临床试验的患者选择策略。