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

在过去的十年里，已经批准了几种新的转移性癌症患者的治疗方案 耐阉割前列腺癌(MCRPC)，延长总生存期。然而，mCRPC没有治愈的方法， 开发新的治疗策略是至关重要的。阿比特龙和苯扎鲁胺是两种药物 靶向雄激素受体(AR)信号通路，延长患者生存时间，证实了 尽管雄激素配体水平被去势，AR仍然是mCRPC的驱动因素。在这个过程中，有几种机制在演变 进展到mCRPC和对阿比特龙/苯扎鲁胺的耐药性，阿比特龙/苯扎鲁胺具有维持AR信号的功能。这些 包括AR的扩增，AR的配体结合域的突变，以及结构性活性的出现 另一种拼接的AR变体。这表明，去除mCRPC中AR表达的方法和耗竭 持续的AR信号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 评价两种去除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，已经通过了一项I期研究，并在一项重大的临床试验中显示出良好的临床反应 经过预处理的mCRPC种群。重要的是，Ionis-AR-2.5-Rx针对全长、突变和剪接变体形式 应变率。我们还进行了一项重大努力，以开发PROTAC(针对嵌合体的蛋白质分解)AR 通过将AR蛋白靶向E3泛素连接酶来降解这种功能。我们共同假设，消融 通过ASOS或PROTAC降解物靶向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： 目的1：评估下一代AR ASO的Ionis-AR-2.5Rx与苯扎鲁胺在Ib/II期的联合应用 治疗mCRPC的临床试验。在这里，我们将通过以下方式继续Ionis-AR-2.5-Rx的临床开发 联合使用苯扎鲁胺进行试验(ARRO-CITO)治疗化疗初治的mCRPC患者。 反应的分子生物标记物将通过综合临床测序从 审判。这一目的将为mCRPC的AR消融策略提供临床概念验证。 目的2：开发有效的口服生物降解剂，并研究其作用机制。作为一秒钟 为了减少AR水平，我们将通过逐步的药物开发来开发一种PROTAC AR降解剂 并确定其体外作用机制。 目的3：评估前列腺癌临床前模型中的AR降解物以选择I期临床候选 在mCRPC进行试验。我们将在这一目标的第一部分进行活体实验，以评估药物动力学， 我们的顶级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， 我们的先导化合物用于mCRPC患者，代表着AR降解剂进入临床试验的第一个进展。 这些研究将导致开发两种治疗方法来消融mCRPC和mCRPC的AR水平 防止通过此驱动程序路径继续发送信号。

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.