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

在过去的十年中，已经批准了几种新的治疗方案，用于转移性肝癌患者。 去势抵抗性前列腺癌（mCRPC），延长总生存期。然而，mCRPC没有治愈方法， 并且开发新的治疗策略是至关重要的。阿比特龙和恩杂鲁胺是两种药物 靶向雄激素受体（AR）信号通路，延长患者生存期，证实了这一观点， 尽管雄激素配体水平达到去势水平，但AR仍然是mCRPC的驱动因素。在此期间， 进展为mCRPC和对阿比特龙/恩杂鲁胺耐药，其功能是维持AR信号传导。这些 包括AR的扩增、AR的配体结合结构域的突变以及组成性活性的AR的出现。 选择性剪接的AR变体。这表明，消除mCRPC中AR表达并消耗AR的方法是有效的。 持续的AR信号传导可有效地为患者提供进一步的存活益处。在这个项目中，我们将 评价两种消融mCRPC中AR的方法：AR反义寡核苷酸（ASO）和AR降解剂。 AR阿索，IONIS-AR-2.5-Rx，已经通过了I期研究，并在严重不良反应中显示出有希望的临床反应。 预治疗mCRPC人群。重要的是，IONIS-AR-2.5-Rx靶向全长、突变体和剪接变体形式 的AR。我们还进行了一项重大努力，开发PROTAC（PROteolysis Targeting Chimeric）AR 通过将AR蛋白靶向E3泛素连接酶发挥功能的降解剂。我们共同假设消融术 通过靶向AR的AS 0或PROTAC降解剂，是一种非常有吸引力的治疗方法， mCRPC，我们将通过以下特定目的进行测试： 目的1：在Ib/II期研究中评价IONIS-AR-2.5Rx（一种新一代AR阿索）与Enzalutamide联合治疗 治疗mCRPC的临床试验。在这里，我们将继续IONIS-AR-2.5-Rx的临床开发， 在未经化疗的mCRPC患者中进行了一项试验（ARRO-CITO）联合enzalutamide。 将通过对肿瘤的综合临床测序来鉴定缓解的分子生物标志物， 审判该目的将为mCRPC中的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可利用的AR降解剂并研究其作用机制。作为第二 为了减少AR水平，我们将通过逐步药物开发开发PROTAC AR降解剂 在体外对其作用机制进行了研究。 目的3：评价前列腺癌临床前模型中的AR降解剂，以选择I期临床试验的候选药物 mCRPC试验。我们将在本目标的第一部分进行体内实验，以评估药代动力学， 药效学和抗肿瘤活性。随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融mCRPC中的AR水平， 阻止通过这条驱动路径的持续信号传递。

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.