Targeting the DNA Damage Response in CDK12-Mutant Prostate Cancer

项目摘要 前列腺癌是美国男性癌症死亡的第二大常见原因。而 早期前列腺癌通常对激素治疗有反应，一部分发展到无法治愈的状态 被称为去势抵抗性前列腺癌（CRPC），它对标准激素治疗有抵抗力。新 迫切需要用于CRPC的分子定义亚群的治疗剂。细胞周期蛋白突变 依赖性激酶1 - 2（CDK 1 - 2），一种转录相关的蛋白激酶，在1-2%的局部 前列腺癌和6-8%的CRPC。确定在临床上有效的治疗方法， mCRPC的侵袭性分子亚型仍然是迫切的和未满足的临床需求。 有趣的是，CDK 12的突变与独特的肿瘤基因组特征相关，包括 全基因组的串联重复模式，癌基因的扩增，隐蔽的内部基因的利用， 多聚腺苷酸化位点和基因融合频率增加。其中一些功能已被 在其他情况下与DNA复制应激（RS）增加有关，这是由异常起源引起的 或者当DNA复制叉遇到DNA损伤或转录复合物停滞时。下 在正常情况下，RS反应是通过ATR/Chk 1激酶途径的信号传导激活的， 协调DNA修复事件，促进复制叉重新启动。在RS升高的情况下， 这种情况发生在某些癌症中，生存对ATR/Chk 1信号传导的依赖性增加。的确， 几种ATR抑制剂（ATRi）目前正处于临床开发中，并且在I/II期中显示出有希望的活性 在人群中进行试验。 该项目的假设是CDK 12突变型前列腺癌与RS增加相关， 从而导致对ATRi的敏化。通过以下目标，我们探索机制驱动 ATRi和聚（ADP-核糖）聚合酶抑制剂（PARPi）在CDK 12突变型前列腺癌中的应用。 首先，在目标1中，我们使用细胞系模型和前列腺癌组织的免疫染色来确定是否 CDK 12丢失与RS标志物表达增加相关。接下来，在目标2中，我们测试ATRi， 在CDK 12-突变前列腺的体外和体内模型中单独治疗或与PARPi组合 癌总之，这个探索性的项目旨在为生物标记选择的设计奠定框架 ATRi单药治疗和/或联合治疗CDK 12改变的mCRPC的临床试验， 这种对当前治疗反应较差的侵袭性mCRPC亚组的临床实践范例 标准疗法

PROJECT SUMMARY Prostate cancer is the second most common cause of cancer death among men in the United States. While early-stage prostate cancers often respond to hormonal therapy, a subset progresses to an incurable state known as castration-resistant prostate cancer (CRPC), which is resistant to standard hormonal therapies. New therapeutic agents for molecularly-defined subsets of CRPC are urgently needed. Mutations in cyclin dependent kinase 12 (CDK12), a transcription-associated protein kinase, are found in 1-2% of localized prostate cancer and 6-8% of CRPC. The identification of therapies that are effective in this clinically aggressive molecular subtype of mCRPC remains a pressing and unmet clinical need. Intriguingly, mutations in CDK12 are associated with distinctive tumor genomic features, including a genome-wide pattern of tandem duplications, the amplification of oncogenes, the utilization of cryptic internal polyadenylation sites, and an increased frequency of gene fusions. Several of these features have been associated in other contexts with increased DNA replication stress (RS), which arises from aberrant origin firing or when DNA replication forks encounter DNA damage or stalled transcriptional complexes. Under normal conditions, the RS response is activated by signaling through the ATR/Chk1 kinase pathway, leading to coordinated DNA repair events that promote replication fork re-start. Under conditions of elevated RS, which occur in some cancers, there is increased dependence on ATR/Chk1 signaling for survival. Indeed, several ATR inhibitors (ATRi) are now in clinical development and have shown promising activity in Phase I/II trials in unselected populations. The hypothesis underlying this project is that CDK12-mutant prostate cancer is associated with increased RS, thereby resulting in a sensitization to ATRi. Through the following aims, we explore the mechanism-driven application of ATRi and poly(ADP-ribose) polymerase inhibitors (PARPi) in CDK12-mutant prostate cancer. First, in Aim 1, we use cell line models and immunostaining of prostate cancer tissues to determine whether CDK12 loss is associated with the increased expression of RS markers. Next, in Aim 2, we test ATRi as monotherapy or in combination with PARPi in both in vitro and in vivo models of CDK12-mutant prostate cancer. Together, this exploratory project aims to lay the framework for the design of biomarker-selected clinical trials of ATRi monotherapy and/or combination therapy for CDK12-altered mCRPC and to influence clinical practice paradigms for this aggressive subset of mCRPC that is poorly responsive to the current standard therapies.