Abstract ND02: GDC-2992: A heterobifunctional Androgen Receptor (AR) antagonist and degrader for the treatment of AR wild-type and mutant prostate cancer

IF 16.6 1区 医学 Q1 ONCOLOGY
Ciara Metcalfe, Wei Zhou, Darlene Dela Cruz, Thomas Hunsaker, Pablo Saenz-Lopez Larrocha, Elizabeth Levy, Bu-Er Wang, Tonia Hafner, Nayan Chaudhary, Marc Hafner, Kalpit Shah, Elisia Villemure, Yuxiang Zheng, Jodie Pang, Udi Segal
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引用次数: 0

Abstract

Prostate cancer is the second most commonly diagnosed cancer in men, with 1 in 8 men being diagnosed with prostate cancer in his lifetime. AR is a hormone-activated transcription factor that promotes cell growth and survival in the normal prostate, and AR signaling is a key driver of cell proliferation in prostate cancer. Inhibition of AR signaling is a mainstay of current prostate cancer treatment, however, patients often develop resistance to these therapies through mechanisms that retain dependency on AR signaling. GDC-2992 (also known as RO7656594) is a potent, orally bioavailable, heterobifunctional molecule that inhibits AR signaling by binding to both AR and the E3 ubiquitin ligase cereblon (CRBN), resulting in ubiquitination and subsequent degradation of AR. GDC-2992 inhibits AR signaling in the context of wild-type AR and AR proteins with mutations associated with resistance to standard-of-care AR signaling inhibitors (ARSIs). Unlike ARSIs, GDC-2992 does not display evidence of agonism against any AR variants evaluated. Co-treatment of GDC-2992 with the CRBN ligand pomalidomide prevents AR degradation mediated by GDC-2992 in vitro, supporting the role of CRBN in GDC-2992-mediated AR degradation. Importantly however, anti-proliferative potential of GDC-2992 is maintained even when degradation is attenuated, suggesting that the mechanism of GDC-2992 includes competitive AR antagonism in addition to degradation. In vivo, GDC-2992 decreases circulating PSA and inhibits prostate tumor growth in a dose responsive manner. The totality of in vitro and in vivo preclinical data supports that GDC-2992 represents a compelling advance over standard-of-care ARSIs. An ongoing Phase I dose-escalation and expansion study will assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of GDC-2992 in patients with advanced or metastatic prostate cancer who have previously received AR-targeted therapy [NCT05800665]. By providing more complete and sustained AR inhibition, GDC-2992 has the potential to reduce the occurrence of treatment-resistance and disease relapse in prostate cancer. Citation Format: Ciara Metcalfe, Wei Zhou, Darlene Dela Cruz, Thomas Hunsaker, Pablo Saenz-Lopez Larrocha, Elizabeth Levy, Bu-Er Wang, Tonia Hafner, Nayan Chaudhary, Marc Hafner, Kalpit Shah, Elisia Villemure, Yuxiang Zheng, Jodie Pang, Udi Segal. GDC-2992: A heterobifunctional Androgen Receptor (AR) antagonist and degrader for the treatment of AR wild-type and mutant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr ND02.
ND02: GDC-2992:异功能雄激素受体(AR)拮抗剂和降解剂,用于治疗AR野生型和突变型前列腺癌
前列腺癌是男性中第二常见的癌症,每8个男性中就有1个被诊断患有前列腺癌。AR是一种激素激活的转录因子,可促进正常前列腺细胞的生长和存活,而AR信号传导是前列腺癌细胞增殖的关键驱动因素。抑制AR信号传导是当前前列腺癌治疗的主要手段,然而,患者往往通过依赖AR信号传导的机制对这些治疗产生耐药性。GDC-2992(也称为RO7656594)是一种有效的、口服生物利用的异功能分子,通过结合AR和E3泛素连接酶小脑(CRBN)来抑制AR信号传导,导致AR的泛素化和随后的降解。GDC-2992在野生型AR和AR蛋白中抑制AR信号传导,这些蛋白的突变与对标准治疗AR信号抑制剂(ARSIs)的抗性相关。与arsi不同,GDC-2992没有显示出对任何AR变异的激动作用。GDC-2992与CRBN配体pomalidomide共处理可在体外阻止GDC-2992介导的AR降解,支持CRBN在GDC-2992介导的AR降解中的作用。然而,重要的是,即使降解减弱,GDC-2992的抗增殖潜能仍保持不变,这表明GDC-2992的机制除了降解外还包括竞争性AR拮抗。在体内,GDC-2992以剂量响应的方式降低循环PSA并抑制前列腺肿瘤生长。总的体外和体内临床前数据支持GDC-2992代表了标准治疗arsi的一个令人信服的进步。正在进行的一期剂量递增和扩展研究将评估GDC-2992在先前接受ar靶向治疗的晚期或转移性前列腺癌患者中的安全性、耐受性、药代动力学和初步抗肿瘤活性[NCT05800665]。通过提供更完整和持续的AR抑制,GDC-2992有可能减少前列腺癌治疗耐药和疾病复发的发生。引文格式:Ciara Metcalfe, Wei Zhou, Darlene Dela Cruz, Thomas Hunsaker, Pablo Saenz-Lopez Larrocha, Elizabeth Levy, Bu-Er Wang, Tonia Hafner, Nayan Chaudhary, Marc Hafner, Kalpit Shah, Elisia Villemure,郑雨香,Jodie Pang, Udi Segal。GDC-2992:一种异功能雄激素受体(AR)拮抗剂和降解剂,用于治疗AR野生型和突变型前列腺癌[摘要]。摘自:《2025年美国癌症研究协会年会论文集》;第二部分(最新进展,临床试验,并邀请s);2025年4月25日至30日;费城(PA): AACR;中国癌症杂志,2015;35(8):391 - 391。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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