Correlative efficacy, biomarker, and mechanistic studies associated with a phase Ib/II clinical trial of treating mCRPC patients with enzalutamide and Venetoclax

前列腺癌（PCa）是一种异质性恶性肿瘤，具有多种表型和功能， 不同的癌细胞雄激素受体（AR）在前列腺癌的发生、发展中起重要作用。 雄激素剥夺疗法（ADT）已被用作晚期PCa的一线治疗，但患者 一般在1-2年内出现去势抵抗。去势抵抗性PCa（CRPC）然后用 抗雄激素，如恩杂鲁胺（Enza）;然而，患者也迅速发展Enza耐药性，在几个 个月ADT和Enza都靶向AR信号传导，其长期疗效取决于PCa细胞表达 AR.然而，我们的工作与许多其他人的工作一起揭示了未经处理的PCa不仅具有AR+，而且 AR-/lo PCa细胞，并且这种AR异质性在CRPC中变得突出。我们最近的工作直接联系到 AR异质性与不同的ADT/Enza反应，并进一步证明AR+和AR-/lo PCa细胞亚群可能在ADT/Enza的压力下共同进化以介导去势抗性。 重要的是，目前大多数抗PCa治疗努力已经针对靶向AR+/hi PCa细胞， 而在很大程度上忽略了AR-/lo细胞群体。由于AR-/lo细胞也可以传播CRPC， 靶向AR-/10群体可以抑制甚至防止对Enza和醋酸阿比特龙的抗性。我们 使用匹配的雄激素依赖性和雄激素非依赖性PCa异种移植物模型的临床前建模 已经确定BCL-2是CRPC的关键驱动因素，也是可行的治疗靶点。基于这种新 知识和有希望的临床前治疗研究，我们假设共靶向AR+/hi（大块肿瘤） 细胞）和AR-/lo PCa细胞的异质性患者肿瘤中使用Enza和BCL-2抑制剂venetoclax将 实现上级临床结果。这一假设目前正在一项新的Ib/II期临床试验中进行检验 由RPCCC的研究小组与AbbVie（NCT 03751436）合作开发。为支持 针对本临床试验的目标，我们在R21项目中提出了以下相关研究，有3个目标： 目的1：确定Enza/venetoclax联合治疗的患者应答者和非应答者; 目的2：确定与患者对Enza/venetoclax反应相关的最佳治疗相关生物标志物 联合治疗;和 目的3：建立临床相关的3D类器官模型，以更好地了解患者的反应性， 肿瘤异质性 意义/影响：我们已经组建了一个由基础科学家和医生科学家组成的优秀团队， 提出了相关研究。该项目的成功完成将促进范式的发展- 筛选和可能改变（Enza-naïve）mCRPC患者的治疗方案。此外，委员会认为， 所提出的研究将对循环肿瘤细胞的应用产生重大影响， 肿瘤反应的药效学建模及其作为新型3D肿瘤模型来源的用途。!

Prostate cancer (PCa) is a heterogeneous malignancy harboring many phenotypically and functionally distinct cancer cells. Androgen receptor (AR) plays an important role in PCa development and progression. Androgen-deprivation therapy (ADT) has been used as the first-line treatment in advanced PCa, but patients generally develop castration resistance within 1-2 years. Castration-resistant PCa (CRPC) is then treated with antiandrogens such as enzalutamide (Enza); however, patients also quickly develop Enza resistance in several months. Both ADT and Enza target AR signaling, whose long-term efficacy depends on PCa cells to express AR. Yet, our work, together with many others', has revealed that untreated PCa harbor not only AR+ but also AR-/lo PCa cells and this AR heterogeneity becomes accentuated in CRPC. Our recent work has directly linked AR heterogeneity to distinct ADT/Enza responses, and further demonstrated that both AR+ and AR-/lo subpopulations of PCa cells may co-evolve under the pressure of ADT/Enza to mediate castration resistance. Critically, most current anti-PCa therapeutic efforts have been directed towards targeting AR+/hi PCa cells, while largely ignoring the AR-/lo cell population. Since AR-/lo cells can also propagate CRPC, simultaneously targeting the AR-/lo population may inhibit and even prevent resistance to Enza and abiraterone acetate. Our pre-clinical modeling using matched androgen-dependent and androgen-independent xenograft models of PCa has identified BCL-2 as a critical driver and also a viable therapeutic target of CRPC. Based on this new knowledge and promising pre-clinical therapeutic studies, we hypothesize that co-targeting AR+/hi (bulk tumor cells) and AR-/lo PCa cells in heterogeneous patient tumors using Enza and the BCL-2 inhibitor venetoclax will achieve superior clinical outcomes. This hypothesis is currently being tested in a new phase Ib/II clinical trial developed by our research group at RPCCC in collaboration with AbbVie (NCT03751436). In support of the objectives for this clinical trial, we propose the following correlative studies in this R21 project, with 3 Aims: Aim 1: To identify patient responders and non-responders to combination Enza/venetoclax therapy; Aim 2: To identify the best treatment related biomarkers associated with patient response to Enza/venetoclax combination therapy; and Aim 3: To establish clinically relevant 3D organoid models to better understand patient responsiveness and tumor heterogeneity. SIGNIFICANCE/IMPACT: We have assembled an outstanding team of basic and physician scientists for the proposed correlative studies. Successful completion of this project will facilitate the development of paradigm- sifting and potentially practice-changing treatment regimens for (Enza-naïve) mCRPC patients. Furthermore, the proposed studies will have significant impact on the application of circulating tumor cells to pharmacodynamic modeling of tumor response and their use as a source of novel 3D tumor models. !