ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer

ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点

• 批准号: 10304098
• 负责人: Leigh Ellis
• 金额: $ 27.12万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-08 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10304098
• 关键词: ATR gene; Adopted; Androgen Receptor; Automobile Driving; Basal Cell; CRISPR/Cas technology; Cancer Patient; Carboplatin; Castration; Cells; Characteristics; Clinical; Clinical Trials; Combined Modality Therapy; DNA Damage; DNA Repair; DNA Repair Inhibition; DNA Repair Pathway; Data; Dependence; Disease; Double Strand Break Repair; EZH2 gene; Early identification; Enhancers; Epigenetic Process; Frequencies; Genes; Genetic; Homologous Gene; Hypersensitivity; Immunotherapy; Intercept; KRP protein; Knowledge; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Mitotic Checkpoint; Modeling; Molecular; Multi-Institutional Clinical Trial; Mus; Neurosecretory Systems; Nonhomologous DNA End Joining; Outcome; Pathway interactions; Patients; Phenotype; Phosphotransferases; Pre-Clinical Model; Predisposition; Prostate; Protein Inhibition; Protein-Serine-Threonine Kinases; Quality of life; RB1 gene; Receptor Signaling; Research Personnel; Resistance; Retinoblastoma; Sampling; Signal Transduction; TP53 gene; Testing; Therapeutic; Update; Validation; Work; androgen deprivation therapy; checkpoint therapy; docetaxel; ds-DNA; functional genomics; genome-wide; immune checkpoint blockade; immunogenicity; inhibitor/antagonist; innate immune pathways; innovation; loss of function; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; pre-clinical; prostate cancer cell; prostate cancer cell line; receptor expression; repaired; resistance mechanism; resistance mutation; response; stem cells; synergism; therapeutic target; therapy resistant; treatment strategy; tumor

PROJECT SUMMARY Metastatic prostate cancer (mPCa) is incurable and responsible for the majority of PC associated mortality. Therefore, there is a critical need to identify drivers of mPCa to enable early identification and interceptive therapeutic strategies to provide durable responses in patients. Androgen deprivation therapy (ADT) is the primary line of treatment for mPCa. ADT initially extends survival but is not curative as the patient’s tumor acquires castration resistance (mCRPC). A majority of mCRPC remain dependent on the function of the androgen receptor (AR), though due to the inclusion of more potent AR antagonist (eg: enzalutamide) has led to the emergence, in a subset of cases (approximately 20%), of resistance mechanisms independent of AR activity (CRPC-AI). CRPC-AI adapt to ADT via lineage plasticity rather than a result of resistant mutations, adopting a phenotype no longer reliant on AR expression and signaling. These tumors may display neuroendocrine features, a stem or basal cell-like phenotype, altered kinase signaling, and characteristic epigenetic alterations. Recently, we and others have characterized the molecular landscape of CRPC-AI and have identified and validated new therapeutic targets and drivers, including loss of Retinoblastoma-1 (RB) and TP53, and induction of specific epigenetic/reprogramming factors such as (Enhancer of Zeste Homolog 2) EZH2 and SOX2. Additionally, our work validated the importance of EZH2 reprogramming downstream of RB1 loss, driving lineage plasticity and resistance to ADT. Moreover, inhibition of EZH2 enabled lineage reversal and re-sensitized RB loss prostate cancer to ADT. Importantly, recent data from patients with mCRPC identified RB genetic aberrations as the strongest predictor of poor outcome. These data implicate RB as a dominant molecular mechanism driving lethal prostate cancer. Currently there is no therapeutic option to provide durable response in patients with RB loss-of-function (LOF). Therefore, there is a critical need to delineate downstream effectors of RB LOF so that therapeutic targets can be identified and validated in clinical trials. Specific to this application, our functional genomic screen has identified dependence on DNA damage repair kinases – specifically – ATR. This proposed work is innovative because it will provide deeper mechanistic knowledge of drivers of RB deficient prostate cancer and therapeutic options towards a currently untreatable phenotype. Through this work we will validate the ability of DDR kinase targeting to exacerbate DDR deficiency and to generate hypersensitivity in RB-deficient prostate models (Aim 1), determine the correlation between RB function, HR proficiency and response to M6620+carboplatin and docetaxel+carboplatin in preclinical models and clinical samples (Aim 2), and evaluate synergy of ATR kinase inhibition, EZH2 inhibition, and immune checkpoint blockade therapy in pre-clinical RB-deficient prostate mouse models (Aim 3). Ultimately, this information will enable us to gather sufficient preliminary evidence to make a compelling case to commence investigator-initiated multi-center clinical trials.

项目摘要 转移性前列腺癌（MPCA）是无法治愈的，并且负责大多数PC相关的死亡率。 因此，迫切需要确定MPCA的驱动因素以实现早期识别和拦截 提供持久反应的治疗策略。雄激素剥夺疗法（ADT）是 MPCA的主要治疗线。 ADT最初延长生存，但由于患者的肿瘤而无法治愈 获得cast割抵抗力（MCRPC）。大多数MCRPC仍然取决于雄激素的功能 接收器（AR），尽管由于包含了更多潜在的AR拮抗剂（例如：enzalutamide）导致了 在一部分情况下（约20％）的出现抗性机制与AR活性无关 （CRPC-AI）。 CRPC-AI通过谱系可塑性适应ADT，而不是抗性突变的结果 表型不再与AR表达和信号传导相关。这些肿瘤可能显示神经内分泌特征， 茎或碱性细胞样表型，激酶信号的改变以及特征性表观遗传改变。最近， 我们和其他人的特征是CRPC-AI的分子景观，并确定并验证了新的。 治疗靶标和驱动因素，包括视网膜母细胞瘤-1（RB）和TP53的丧失以及特定的诱导 表观遗传/重编程因素，例如（Zeste同源2的增强子）EZH2和SOX2。 此外，我们的工作验证了RB1损失下游EZH2重编程的重要性，驾驶 谱系可塑性和对ADT的抵抗力。此外，抑制EZH2启用了谱系逆转和重新敏感 RB损失前列腺癌至ADT。重要的是，来自MCRPC患者的最新数据确定了RB遗传 畸变是不良预后的有力预测指标。这些数据暗示RB是主要的分子 驱动致命前列腺癌的机制。目前没有提供耐用的治疗选择 RB功能丧失（LOF）的患者的反应。因此，迫切需要描述 RB LOF的下游效应，以便可以在临床中识别和验证治疗靶标 试验。特定于此应用，我们的功能性基因组筛选已经确定了对DNA损伤的依赖性 修复激酶 - 特别是ATR。这项提出的工作具有创新性，因为它将提供更深的机械性 了解RB缺乏前列腺癌的驱动因素以及目前不可治疗的治疗选择 表型。通过这项工作，我们将验证DDR激酶靶向加剧DDR缺乏的能力 并在RB缺陷的前列腺模型中产生超敏反应（AIM 1），请确定RB之间的相关性 临床前模型中的功能，熟练度和对M6620+Carboplatin+Carboplatin的反应 和临床样品（AIM 2），并评估ATR激酶抑制，EZH2抑制和免疫的协同作用 检查点封锁治疗前临床前RB缺乏前列腺小鼠模型（AIM 3）。最终，这个 信息将使我们能够收集足够的初步证据来提出令人信服的案例 研究者发动的多中心临床试验。