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