Combining an α<sub>v</sub>β<sub>6</sub>-Targeted <sup>177</sup>Lu-Based Peptide Receptor Radionuclide Therapy with Olaparib to Boost Therapeutic Efficacy in Pancreatic Cancer.
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- Also identified by DOI 10.2967/jnumed.125.271137.
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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 α<sub>v</sub>β<sub>6</sub> 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<sub>v</sub>β<sub>6</sub> using peptide receptor radionuclide therapy (PRRT) in combination with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. <b>Methods:</b> We combined the α<sub>v</sub>β<sub>6</sub>-targeted PRRT agent [<sup>177</sup>Lu]Lu-DOTA-ABM-5G with olaparib, a PARP inhibitor. The combination therapy was evaluated in vitro in α<sub>v</sub>β<sub>6</sub>-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. <b>Results:</b> In vitro, the [<sup>177</sup>Lu]Lu-DOTA-ABM-5G was rapidly internalized by α<sub>v</sub>β<sub>6</sub>-positive pancreatic Capan-1 cells; in vivo, it was taken up by Capan-1 xenograft tumors in mice. Combination treatment with [<sup>177</sup>Lu]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. <b>Conclusion:</b> The combination of α<sub>v</sub>β<sub>6</sub>-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.