Targeting the DNA Damage Repair Pathway in Non-Castrate Prostate Cancers

项目摘要/摘要 BRCA2、ATM和其他DNA损伤的种系(~12%)和体细胞(~25%)改变的频率 耐去势前列腺癌(CRPC)患者的修复(DDR)基因已被描述。DDR- 改变的PC转移进展率更高，对雄激素剥夺的反应减弱 治疗(ADT)。在风险较低的非去势PC中，DDR改变的频率约为10%-15% (主要是生殖系)。我们建议可以通过治疗获得特殊的反应或治愈。 目的是进一步抑制DDR途径(PARP抑制)和ADT，根治性前列腺切除术 (RP)和扩大淋巴清扫(LND)，以及可见转移灶的放射治疗。 我们团队的经验表明，在非去势、高风险的情况下，积极的、多模式的治疗 局限性和少转移性前列腺癌可导致前列腺的病理完全反应，以及 持久的PSA缓解(用非去势睾酮检测不到PSA)。受到这一点和 在DDR改变的CRPC中看到奥拉帕利的活性，该项目的目标1提出了一种新的、灵活的、随机的、 多臂临床试验平台(MetaCURE试验)，用于测试PARP靶向系统治疗的能力 抑制剂与ADT+阿比特龙、RP和LND，以及可见转移的放射治疗，以消除PC 有和没有DDR通路改变的患者(根据通路中单个基因的改变进行分类)。 该协议得到了Janssen制药公司的支持，该试验于2018年第二季度开始。新奇的结构 允许添加新的治疗武器，而无需编写新的方案。 目标2和目标3是由MetaCURE平台预期嵌入的相关科学计划在 哪些肿瘤组织样本(来自诊断性前列腺活检、RP、淋巴结和转移部位)以及 治疗前后将系统地采集用于无细胞DNA分析的血液样本。所有患者 将使用MSK-IMPACT进行成对的肿瘤/生殖系测序，以确认局部肿瘤分析的结果 并评估DDR途径突变的杂合性丢失。用完整的exome进行深入分析 将对特殊应答者/无应答者进行测序和RNA-Seq，以确定潜在的 反应/耐药的生物标志物以及在非DDR改变的肿瘤中反应的新的基因类型 DDR-已更改状态。对AIM 3中无细胞DNA的分析将通过跟踪DDR水平来补充AIM 2 以评估微小残留病并确定潜在的耐药机制。这个 与PARP抑制和ADT耐药性相关的可操作突变的评估 对基因组突变负担的治疗效果，以及本赠款中其他项目的观察(项目1和 项目3)将为MetaCURE试验中后续治疗队列的开发提供信息。

PROJECT SUMMARY/ABSTRACT The frequency of germline (~12%) and somatic (~25%) alterations in BRCA2, ATM, and other DNA damage repair (DDR) genes in patients with castration-resistant prostate cancer (CRPC) has been described. DDR- altered PC has higher metastatic progression rates, and an attenuated response to androgen deprivation therapy (ADT). The frequency of DDR alterations in poor-risk non-castrate PC is approximately 10-15% (predominantly germline). We propose that exceptional responses or cure may be obtained with therapy targeted at further inhibition of the DDR pathway (PARP inhibition) together with ADT, radical prostatectomy (RP) and extended lymph node dissection (LND), and radiation to visible metastases. Our teams’ experience has demonstrated that aggressive, multimodality therapy in non-castrate, high-risk localized and oligometastatic PC can result in pathologic complete responses in the prostate, along with durable PSA remissions (undetectable PSA with non-castrate testosterone). Encouraged by this and the activity seen with olaparib in DDR-altered CRPC, Aim 1 of this project proposes a novel, flexible, randomized, multi-arm clinical trial platform (MetaCURE trial) to test the ability of targeted systemic therapy with a PARP inhibitor, together with ADT+abiraterone, RP and LND, and radiation to visible metastases, to eliminate PC in patients with and without DDR pathway alterations (as classified by alterations in single genes in the pathway). The protocol is supported by Janssen Pharmaceuticals and the trial opened Q2 2018. The novel structure allows new treatment arms to be added without writing a new protocol. Aims 2 and 3 are enabled by the MetaCURE platform’s prospectively embedded correlative science program in which tumor tissue samples (from diagnostic prostate biopsy, RP, lymph nodes, and metastatic sites) and blood samples for cell-free DNA analysis will be systematically collected before and after therapy. All patients will have paired tumor/germline sequencing using MSK-IMPACT to confirm the result of local tumor profiling and to assess for loss of heterozygosity of DDR pathway mutations. In-depth analyses with whole exome sequencing and RNA-Seq will be carried out on exceptional responders/nonresponders to identify potential biomarkers of response/resistance and in non-DDR altered tumors that respond, new genotypes that reflect DDR-altered status. Analysis of cell-free DNA in Aim 3 will complement Aim 2, by tracking levels of DDR alterations to assess for minimal residual disease and to identify potential mechanisms of drug resistance. The evaluation of actionable mutations associated with resistance to PARP inhibition and ADT, the evaluation of treatment effect on genomic mutation burden, and observations from other projects in this grant (Project 1 and Project 3) will inform the development of subsequent treatment cohorts in the MetaCURE trial.