Abstract 440: Targeting oncogenic TBRI signaling inhibits androgen-independent prostate cancer growth and metastasis.

Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains the primary cause of prostate cancer-related mortality. Despite available treatments, the molecular mechanisms underlying tumor invasion and metastasis are not fully understood, highlighting the need for novel therapeutic strategies. In this study, we developed fully human monoclonal antibodies (mAbs) that prevent the proteolytic cleavage of the transforming growth factor-beta (TGFβ) type I receptor (TβRI) by steric hindrance. This cleavage, mediated by the metalloprotease ADAM17 (a disintegrin and metalloprotease domain 17), also known as TACE, results in the generation of a soluble intracellular domain (TβRI-ICD) that translocates to the nucleus of castration-resistant prostate cancer (CRPC) cells and promotes epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. High levels of TGFBR1 were found to correlate with poor survival in two independent clinical cohorts of patients with mCRPC, and a strong positive association between TGFBR1 and ADAM17 expression was observed. In a preclinical human mCRPC mouse model, treatment with our therapeutic mAbs effectively prevented nuclear accumulation of TβRI-ICD, inhibited EMT, and suppressed tumor growth, invasion, and metastasis. Notably, the therapeutic effect was comparable to that of docetaxel, a current standard-of-care chemotherapy, and without noticeable side effects. These findings suggest that targeting TβRI cleavage using specific mAbs offers a novel precision medicine approach for mCRPC. By selectively blocking the pro-metastatic activity of TβRI-ICD without disrupting physiological TGFβ signaling, this strategy may provide a safer and more effective alternative to existing therapies for advanced prostate cancer. Citation Format: Per Flodbring Larsson, Alexej Schmidt, Yabing Mu, Guangxiang Zang, Jie Song, Vishnupriya Gajavilli, Junting Tao, Olena Rahkimova, Madelene Ericsson, Karthik Aripaka, Sofia Halin Bergstroem, Wei Yuan, Denisa Bogdan, Aaron Zhang, Jon Welti, Anders Bergh, Johann de Bono, Carl-Henrik Heldin, Marene Landstroem. Targeting oncogenic TBRI signaling inhibits androgen-independent prostate cancer growth and metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 440.