Abstract
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 αvβ6 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 αvβ6 using peptide receptor radionuclide therapy (PRRT) in combination with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Methods: We combined the αvβ6-targeted PRRT agent [177Lu]Lu-DOTA-ABM-5G with olaparib, a PARP inhibitor. The combination therapy was evaluated in vitro in αvβ6-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 αvβ6-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 αvβ6-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.