Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for Castration-Resistant Prostate Cancer

过去十年，多种针对转移性患者的新治疗方案获得批准 去势抵抗性前列腺癌（mCRPC）可延长总体生存期。然而，mCRPC 尚无治愈方法， 开发新的治疗策略至关重要。阿比特龙和恩杂鲁胺是两种药物 针对延长患者生存期的雄激素受体 (AR) 信号通路，证实了以下观点： 尽管雄激素配体水平被去势，但 AR 仍然是 mCRPC 的驱动因素。多种机制在此过程中演变 进展为 mCRPC 以及对维持 AR 信号传导的阿比特龙/恩杂鲁胺耐药。这些 包括 AR 的扩增、AR 配体结合域的突变以及组成型活性的出现 选择性剪接的 AR 变体。这表明消除 mCRPC 中 AR 表达并消除 持续的 AR 信号传导可能有效地为患者提供进一步的生存益处。在这个项目中，我们将 评估两种消除 mCRPC 中 AR 的方法：AR 反义寡核苷酸 (ASO) 和 AR 降解剂。 AR ASO IONIS-AR-2.5-Rx 已通过 I 期研究，并在大量研究中显示出有希望的临床反应 预处理的 mCRPC 群体。重要的是，IONIS-AR-2.5-Rx 针对全长、突变体和剪接变体形式 的 AR。我们还大力开发 PROTAC（蛋白水解靶向嵌合体）AR 通过将 AR 蛋白靶向 E3 泛素连接酶发挥作用的降解剂。我们一起假设消融 通过针对 AR 的 ASO 或 PROTAC 降解剂来治疗 AR 是一种非常有吸引力的治疗方法 mCRPC，我们将通过以下具体目标进行测试： 目标 1：在 Ib/II 期中评估下一代 AR ASO IONIS-AR-2.5Rx 与恩杂鲁胺的组合 治疗 mCRPC 的临床试验。在这里，我们将继续进行 IONIS-AR-2.5-Rx 的临床开发 在未接受化疗的 mCRPC 患者中进行一项联合恩杂鲁胺试验 (ARRO-CITO)。 将通过对来自肿瘤的综合临床测序来鉴定反应的分子生物标志物 审判。该目标将为 mCRPC 中的 AR 消融策略提供临床概念验证。 目标 2：开发有效的、口服生物可利用的 AR 降解剂并研究其作用机制。作为第二个 为了消除 AR 水平，我们将通过逐步药物开发来开发 PROTAC AR 降解剂 体外处理并确认其作用机制。 目标 3：评估前列腺癌临床前模型中的 AR 降解剂，以选择 I 期临床候选药物 mCRPC 试验。我们将在本目标的第一部分中进行体内实验来评估药代动力学， 我们顶级 AR 降解剂的药效学和抗肿瘤活性。然后将启动第一阶段研究 我们在 mCRPC 患者中的先导化合物，代表了 AR 降解剂首次进入临床试验。 这些研究将导致开发两种治疗方法来消除 mCRPC 和 防止通过该驱动程序路径持续发出信号。

The past decade has brought the approval of several new treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) that extend overall survival. However, there is no cure for mCRPC, and development of novel therapeutic strategies is critical. Abiraterone and enzalutamide are two agents targeting the androgen receptor (AR) signaling pathway that extend patient survival, confirming the notion that AR remains a driver of mCRPC despite castrate levels of androgen ligands. Several mechanisms evolve during progression to mCRPC and resistance to abiraterone/enzalutamide that function to maintain AR signaling. These include amplification of AR, mutation of the ligand-binding domain of AR, and emergence of constitutively active alternatively spliced AR variants. This suggests that methods to ablate AR expression in mCRPC and deplete continued AR signaling may be effective in providing further survival benefit to patients. In this project, we will evaluate two approaches to ablate AR in mCRPC: AR antisense oligonucleotides (ASOs) and AR degraders. The AR ASO, IONIS-AR-2.5-Rx, has cleared a Phase I study and showed promising clinical responses in a heavily pretreated mCRPC population. Importantly, IONIS-AR-2.5-Rx targets full-length, mutant, and splice variant forms of AR. We have also undertaken a major effort to develop PROTAC (PROteolysis TArgeting Chimeric) AR degraders that function by targeting AR protein to an E3 ubiquitin ligase. Together, we hypothesize that ablation of AR, through ASOs or PROTAC degraders targeting AR, is a highly attractive therapeutic approach for mCRPC, and we will test this through the following Specific Aims: Aim 1: Evaluate IONIS-AR-2.5Rx, a next-generation AR ASO, in combination with enzalutamide in a Phase Ib/II clinical trial for the treatment of mCRPC. Here, we will continue the clinical development of IONIS-AR-2.5-Rx by performing a trial (ARRO-CITO) in combination with enzalutamide in chemotherapy-naïve mCRPC patients. Molecular biomarkers of response will be identified through integrative clinical sequencing of tumors from the trial. This Aim will provide clinical proof-of-concept for AR ablative strategies in mCRPC. Aim 2: Develop potent, orally bioavailable AR degraders and study their mechanism of action. As a second approach to deplete AR levels, we will develop a PROTAC AR degrader through a stepwise drug development process and confirm its mechanism of action in vitro. Aim 3: Evaluate AR degraders in preclinical models of prostate cancer to select a candidate for a Phase I clinical trial in mCRPC. We will perform in vivo experiments in the first part of this Aim to assess pharmacokinetics, pharmacodynamics, and antitumor activity of our top AR degraders. A Phase I study will then be initiated with our lead compound in mCRPC patients, representing the first advancement of an AR degrader into clinical trials. These studies will lead to the development of two therapeutic approaches to ablate AR levels in mCRPC and prevent continued signaling through this driver pathway.