Abstract 6020: GPC3-targeted radiopharmaceutical therapy for neuroendocrine prostate cancer

Abstract Introduction: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein with minimal expression in normal tissues. Besides hepatocellular carcinoma, upregulation of GPC3 protein has been observed in a significant subset of treatment-emergent neuroendocrine prostate cancer (NEPC), which accounts for to 30% of prostate cancer cases refractory to anti-androgen and other therapies. The differential expression of GPC3 between NEPC cells and normal tissues provides a theranostic opportunity for targeted radiopharmaceutical therapy (RPT). Methods: The novel RPT agent RYZ-GPC3 comprises a small macrocyclic peptide binder with high affinity to GPC3 linked with a tetraxetan moiety capable of chelating a variety of radioisotopes. The expression of GPC3 in NEPC cells was assessed by flow cytometry and immunohistochemistry (IHC). The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR) and radioligand binding assays. In vivo biodistribution of 177LuLu-RYZ-GPC3 and anti-tumor therapy with 177LuLu-RYZ-GPC3 or 225AcAc-RYZ-GPC3 were performed in NEPC xenografts. Results: The novel agent is a highly potent and selective peptide binder to GPC3 of human, mouse and NHP origins, and is compatible with multiple radiometal isotopes. In vivo biodistribution study of 177LuLu-RYZ-GPC3 in GPC3-positive NEPC xenografts showed sustained tumor uptake of 10. 8, 12. 6, 5. 1, and 2. 2 %ID/g at 2, 24, 72 and 168 hours post dose, respectively, with fast renal clearance. Minimal or no uptake was observed in other normal tissues. A single injection of 225AcAc-RYZ-GPC3 (11. 1 kBq) resulted in significant tumor growth inhibition (TGI 109%) with durable regression and prolonged survival. All treatments were well tolerated. Conclusion: Preclinical in vitro and in vivo data demonstrated the potential of the novel binder as a theranostic agent for the treatment of patients with GPC3+ NEPC. Citation Format: Renee Clift, Fanching Lin, Katrina Salvador, Matt Guest, Daniel Kim, Guangzhou Han, Gary Li. GPC3-targeted radiopharmaceutical therapy for neuroendocrine prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6020.