αvβ6-Targeted `[177Lu]Lu-DOTA-ABM-5G` PRRT with Olaparib Boosts Pancreatic Cancer Survival and Cell Death

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies globally, with an urgent need for more effective and less toxic treatments. Current standard-of-care often falls short due to aggressive progression and resistance. Integrin αvβ6, a cell-surface receptor, is significantly overexpressed in several cancers, including PDAC, where it drives invasion and metastasis. This makes αvβ6 an attractive molecular target for both detection and therapy, prompting investigation into targeted approaches like peptide receptor radionuclide therapy (PRRT).

Researchers investigated a combination therapy using the αvβ6-targeted PRRT agent [177Lu]Lu-DOTA-ABM-5G with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. In vitro studies were conducted on αvβ6-positive pancreatic Capan-1 cells to assess cell viability (water-soluble tetrazolium salt 1 assay), apoptosis induction, cell cycle arrest (cell cycle analysis), and double-strand break formation (γ-H2AX foci). In vivo, pharmacokinetic and therapeutic efficacy were evaluated in mice bearing Capan-1 xenograft tumors, comparing combination treatment to control and single-agent arms.

In vitro, [177Lu]Lu-DOTA-ABM-5G was rapidly internalized by αvβ6-positive Capan-1 cells. In vivo, it was effectively taken up by Capan-1 xenograft tumors. The combination treatment of [177Lu]Lu-DOTA-ABM-5G and olaparib significantly reduced cell viability compared to single-agent treatments. This synergistic effect was further evidenced by a significant increase in the percentage of cells in the sub-G1 and G2/M phases, indicating enhanced cell cycle arrest. The combination also resulted in the greatest number of γ-H2AX foci per cell, signifying increased DNA double-strand breaks. In vivo, the combination treatment demonstrated superior efficacy:

It significantly delayed tumor growth progression and improved median survival compared with both control and single-agent treatments, with no observed treatment-related adverse events.