Abstract 958: Effective targeting of pancreatic ductal adenocarcinoma metastases with an integrin αvβ6-targeting peptide-drug conjugate

Abstract

Pancreatic ductal adenocarcinoma (PDAC) exhibits an extremely poor prognosis, with 5 year-survival rates 80% of human PDAC tumors including their paired metastases but is not significantly expressed by healthy pancreas tissue. Thus, αvβ6 represents a promising therapeutic target. We previously developed the αvβ6-specific peptide-drug conjugate (PDC) SG3299, composed of the DNA-binding pyrrolobenzodiazepine (PBD)-based compound tesirine conjugated to the αvβ6-targeting peptide A20FMDV2. Relative to the non-targeting PDC SG3511, SG3299 showed anti-tumor efficacy against αvβ6-positive human PDAC xenografts in immunodeficient mouse models. The present study aimed to evaluate the efficacy of αvβ6-targeted therapy on primary tumors and metastases in an immunocompetent murine model of PDAC. We have previously reported that KPC (Kras-G12D P53-R172H Pdx1-Cre) transgenic mouse PDAC tumors do not express αvβ6, so we ectopically expressed murine integrin-β6 in the TB32043 KPC-derived PDAC cell line, creating the αvβ6-expressing line TB32043mb6S2. When injected orthotopically into immunocompetent C57BL/6 mice, TB32043mb6S2 cells produced primary pancreatic tumors with αvβ6-positive metastases to the liver, peritoneum, and lung. Mice injected orthotopically with TB32043mb6S2 cells exhibited increased primary tumor desmoplasia, increased incidence of peritoneal metastases (100% vs 20%, p Citation Format: Elizabeth R. Murray, Nicholas F. Brown, Philip Howard, Luke Masterson, Francesca Zammarchi, Patrick H. van Berkel, John F. Marshall. Effective targeting of pancreatic ductal adenocarcinoma metastases with an integrin αvβ6-targeting peptide-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 958.