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

基本信息

批准号：
10186723
负责人：
Leigh Ellis
金额：
$ 36.75万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10186723
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 Gene set enrichment analysis 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

项目摘要

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.

项目概要转移性前列腺癌 (mPCa) 无法治愈，并且是大多数 PC 相关死亡的原因。因此，迫切需要识别 mPCa 驱动程序，以便及早识别和拦截为患者提供持久反应的治疗策略是雄激素剥夺疗法（ADT）。 mPCa 的主要治疗方法最初可以延长生存期，但不能治愈患者的肿瘤。获得去势抵抗 (mCRPC) 大部分 mCRPC 仍然依赖于雄激素的功能。受体（AR），尽管由于包含更有效的 AR 拮抗剂（例如：恩杂鲁胺）导致在部分病例（约 20%）中，出现了独立于 AR 活性的耐药机制（CRPC-AI）。CRPC-AI 通过谱系可塑性而不是抗性突变的结果来适应 ADT，采用了表型不再依赖于 AR 表达和信号传导。这些肿瘤可能表现出神经内分泌特征，最近，干细胞或基底细胞样表型、激酶信号传导改变和特征性表观遗传改变。我们和其他人已经描述了 CRPC-AI 的分子景观，并识别和验证了新的治疗靶点和驱动因素，包括视网膜母细胞瘤-1 (RB) 和 TP53 的丧失，以及特异性的诱导表观遗传/重编程因子，例如（Zeste 同源物增强子 2）EZH2 和 SOX2。此外，我们的工作验证了 RB1 丢失下游 EZH2 重编程的重要性，驱动谱系可塑性和 ADT 抗性此外，抑制 EZH2 可以实现谱系逆转和重新敏化。 RB 因 ADT 导致前列腺癌消失重要的是，来自 mCRPC 患者的最新数据确定了 RB 遗传。畸变是不良结果的最强预测因素。这些数据表明 RB 是主要分子。目前还没有提供持久的治疗选择。因此，迫切需要描述 RB 功能丧失（LOF）患者的反应。 RB LOF 的下游效应器，以便在临床中识别和验证治疗靶点针对该应用，我们的功能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 这项提议的工作是创新的，因为它将提供更深入的机制。了解 RB 缺乏型前列腺癌的驱动因素以及目前无法治疗的治疗方案通过这项工作，我们将验证 DDR 激酶靶向加剧 DDR 缺陷的能力。并在 RB 缺乏的前列腺模型中产生超敏反应（目标 1），确定 RB 之间的相关性临床前模型中对 M6620+卡铂和多西他赛+卡铂的功能、HR 熟练程度和反应和临床样本（目标 2），并评估 ATR 激酶抑制、EZH2 抑制和免疫的协同作用在临床前 RB 缺陷的前列腺小鼠模型中进行检查点阻断治疗（目标 3）。信息将使我们能够收集足够的初步证据，以提出令人信服的案件研究者发起的多中心临床试验。