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

项目总结 转移性前列腺癌(MPCA)是不治之症，是PC相关死亡的主要原因。 因此，迫切需要识别MPCA的驱动因素，以便能够及早识别和拦截 治疗策略，为患者提供持久的反应。雄激素剥夺疗法(ADT)是 MPCA的主要治疗路线。ADT最初延长了患者的生存期，但并不像患者的肿瘤那样治愈 获得去势抗性(MCRPC)。大多数mCRPC仍然依赖于雄激素的功能 受体(AR)，尽管由于加入了更有效的AR拮抗剂(如：苯扎鲁胺)已导致 在部分病例中(约20%)出现独立于AR活性的抗性机制 (CRPC-AI)。CRPC-AI通过谱系可塑性而不是耐药性突变来适应ADT，采用了一种 表型不再依赖AR的表达和信号。这些肿瘤可能表现出神经内分泌特征， 干细胞或基底细胞样表型，改变的激酶信号，和特征性的表观遗传改变。最近， 我们和其他人已经表征了CRPC-AI的分子图景，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的缺失，以及诱导特异性 表观遗传/重新编程因子，如(Zust Homolog 2的增强子)EZH2和SOX2。 此外，我们的工作验证了EZH2重新编程在RB1丢失、驱动下游的重要性 谱系可塑性和对ADT的抗性。此外，对EZH2的抑制使谱系逆转和再敏化 RB将前列腺癌转移到ADT。重要的是，来自mCRPC患者的最新数据确定了Rb基因 像差作为不良结局的最强预测因子。这些数据表明Rb是主要的分子 致命性前列腺癌的机制。目前还没有治疗选择来提供持久的 RB功能丧失(LOF)患者的反应。因此，迫切需要划定 Rb LOF的下游效应器，从而可以在临床上识别和验证治疗靶点 审判。具体到这一应用，我们的功能基因组筛选已经确定了对DNA损伤的依赖 修复激酶-具体地说-ATR。这项拟议的工作具有创新性，因为它将提供更深层次的机制 Rb缺陷型前列腺癌的致病因素和治疗选择的知识 表型。通过这项工作，我们将验证DDR激酶靶向加重DDR缺乏的能力 并在Rb缺乏的前列腺模型中产生超敏反应(目标1)，确定Rb与 临床前模型中的功能、HR熟练程度和对M6620+卡铂和多西紫杉醇+卡铂的反应 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 临床前Rb缺陷小鼠模型的检查点阻断治疗(目标3)。归根结底，这 信息将使我们能够收集足够的初步证据，使令人信服的案件开始 研究人员发起的多中心临床试验。

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.