Abstract B017: Evaluation of a first-in-class dual TRPV6/AR inhibitor for the treatment of prostate cancer

Abstract The calcium selective ion channel TRPV6 is an oncochannel that is highly overexpressed in many advanced prostate cancers. The Androgen Receptor (AR) is a key driver of prostate cancer and anti-androgen therapy is a mainstay of current prostate cancer treatment regimes. We have observed that concomitant TRPV6 and AR inhibition is synergistic in prostate cancer cells resulting in a highly anti-proliferative effect. Our preclinical candidate QED-203 inhibits TRPV6-mediated calcium influx with low nM potency and inhibits AR activity. QED-203 maintains effectiveness in prostate cancer cell lines that are resistant to next generation AR inhibitors (e.g. enzalutamide) with multiple resistance mechanisms including the ARV7 variant. QED-203 has high oral bioavailability with a pharmacokinetic profile amenable to once-a-day dosing. QED-203 is well tolerated in rodents with excellent in vivo efficacy in castrated mouse models of prostate cancers, including a PDX model with pronounced resistance to first and second-generation AR inhibitors (HID-28). TRPV6 target engagement has been demonstrated for QED-203 in rodents through changes in urine calcium levels, and via gene expression changes consistent with TRPV6 inhibition in xenograft tumours. QED-203 thus targets a novel dual axis pathway (AR/TRPV6) to supress prostate cancer growth. QED-203 may offer a new opportunity to treat prostate cancer patients who have developed resistance to next generation AR therapies, where there is a clear clinical need for new therapeutic approaches. Citation Format: Gregory R. Monteith, Kimberley Beaumont, Rebecca Pouwer, Rebecca Farrow, Matthew McLachlan, Mei Yeh, Akanksha Upadhyaya, Aaron Gregson, Therese Johnson, Raphael Rahmani, Claire Levrier, Hasanthi Wijesekera, Malika Kumarasiri, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Brian Dymock. Evaluation of a first-in-class dual TRPV6/AR inhibitor for the treatment of prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B017.