Combining an α_vβ₆-Targeted ¹⁷⁷Lu-Based Peptide Receptor Radionuclide Therapy with Olaparib to Boost Therapeutic...

Pancreatic ductal adenocarcinoma is one of the most lethal malignances worldwide, and there remains an urgent need for more effective and less toxic treatment strategies. Integrin α_vβ₆ is a cell-surface receptor that is overexpressed in several malignancies, including pancreatic ductal adenocarcinoma, and plays a key role in invasion and metastasis, making it a promising molecular target for the detection and treatment of many cancers. We investigated a molecularly targeted approach that exploits the overexpression of α_vβ₆ using peptide receptor radionuclide therapy (PRRT) in combination with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Methods: We combined the α_vβ₆-targeted PRRT agent [¹⁷⁷Lu]Lu-DOTA-ABM-5G with olaparib, a PARP inhibitor. The combination therapy was evaluated in vitro in α_vβ₆-positive pancreatic Capan-1 cells by investigating its effect on cell viability, apoptosis induction, cell cycle arrest, and the formation of double-strand breaks. In vivo pharmacokinetic and therapeutic efficacy studies were performed in mice bearing Capan-1 xenograft tumors. Results: In vitro, the [¹⁷⁷Lu]Lu-DOTA-ABM-5G was rapidly internalized by α_vβ₆-positive pancreatic Capan-1 cells; in vivo, it was taken up by Capan-1 xenograft tumors in mice. Combination treatment with [¹⁷⁷Lu]Lu-DOTA-ABM-5G and olaparib significantly reduced cell viability (water-soluble tetrazolium salt 1 assay), significantly increased the percentage of cells in the sub-G1 and G2/M phases (cell cycle analysis), and resulted in the greatest number of γ-H2AX foci per cell compared with single-agent treatment. In vivo, the combination treatment delayed tumor growth progression and significantly improved median survival compared with the control and single-agent treatments, with no observed treatment-related adverse events. Conclusion: The combination of α_vβ₆-targeted PRRT and PARP inhibition enhanced therapeutic efficacy compared with single-agent treatment. These findings warrant further investigation, particularly given the urgent need for improved treatments for pancreatic cancer.