Targeting the DNA Damage Response in CDK12-Mutant Prostate Cancer

靶向 CDK12 突变前列腺癌中的 DNA 损伤反应

• 批准号: 10437891
• 负责人: Kent W Mouw
• 金额: $ 24.39万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437891
• 关键词: Aftercare; Aggressive Clinical Course; Alleles; Androgen Receptor; Biological Assay; Biological Markers; C-terminal; CDC2 gene; CHEK1 gene; Cancer Etiology; Cancer Patient; Cause of Death; Cell Cycle; Cell Line; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Cyclin-Dependent Kinases; DNA Damage; DNA Repair; DNA Repair Disorder; DNA biosynthesis; DNA replication fork; DNA-Directed RNA Polymerase; Dependence; Development; Disease Progression; Event; Gene Expression Profile; Gene Frequency; Gene Fusion; Genes; Genetic Transcription; Genome Stability; Genomics; Immune checkpoint inhibitor; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metastatic to; Modeling; Molecular; Mutation; Oncogenes; PARP inhibition; Pathway interactions; Pattern; Phase I/II Trial; Phenotype; Phosphotransferases; Poly(ADP-ribose) Polymerases; Polyadenylation; Population; Primary Neoplasm; Process; Property; Prostatic Neoplasms; Protein Kinase; Proteomics; Reporter; Resistance; Role; Signal Transduction; Single-Stranded DNA; Site; Small Interfering RNA; Specimen; Suggestion; Testing; Therapeutic Agents; Tissues; United States; Vertebral column; Western Blotting; base; biological adaptation to stress; castration resistant prostate cancer; clinical development; clinical practice; cohort; design; genome-wide; genomic data; homologous recombination; hormone therapy; in vivo; in vivo Model; inhibitor; men; molecular subtypes; mutant; novel therapeutics; potential biomarker; prostate cancer cell line; replication stress; response; small hairpin RNA; targeted agent; targeted treatment; tumor; tumor xenograft

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.

项目总结 前列腺癌是美国男性癌症死亡的第二大常见原因。而当 早期前列腺癌通常对激素治疗有反应，一部分进展到无法治愈的状态。 被称为去势抵抗型前列腺癌(CRPC)，对标准激素疗法具有抵抗力。新的 迫切需要针对CRPC分子定义亚群的治疗药物。细胞周期蛋白的突变 依赖蛋白激酶12(CDK12)是一种转录相关的蛋白激酶，在1-2%的局部性细胞中存在 前列腺癌和6-8%的CRPC。临床上有效的治疗方法的确定 侵袭性分子亚型的mCRPC仍然是一个迫切而未得到满足的临床需求。 有趣的是，CDK12的突变与独特的肿瘤基因组特征有关，包括 全基因组的串联复制模式、癌基因的扩增、隐匿内含子的利用 多腺苷酸化位点，以及基因融合频率的增加。其中几个功能已经 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 启动或当DNA复制叉遇到DNA损伤或转录复合体停滞时。在……下面 正常情况下，RS反应通过ATR/Chk1激酶通路的信号激活，导致 以促进复制分叉重新启动的协调DNA修复事件。在RS升高的情况下， 这发生在一些癌症中，生存对ATR/Chk1信号的依赖增加。的确， 几种ATR抑制剂(ATRI)目前正在临床开发中，并在I/II期显示出良好的活性 在未经选择的人群中进行试验。 这个项目背后的假设是CDK12突变的前列腺癌与RS增加有关， 从而导致对ATRI的敏化。通过以下目标，我们探索了机制驱动 ATRI和聚腺苷二磷酸核糖聚合酶抑制剂在CDK12突变前列腺癌中的应用 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 CDK12缺失与RS标志物表达增加有关。接下来，在目标2中，我们测试ATRI为 单用或联合PARPI治疗CDK12突变前列腺癌的体内外实验研究 癌症。这一探索性项目旨在为生物标志物选择的设计奠定框架。 ATRI单药和/或联合治疗CDK12基因改变的mCRPC的临床试验及其影响 这一积极的mCRPC子集的临床实践范例对当前的 标准疗法。