Abstract 958: Effective targeting of pancreatic ductal adenocarcinoma metastases with an integrin αvβ6-targeting peptide-drug conjugate
Authors: Murray Elizabeth R. , Brown Nicholas F. , Howard Philip , Masterson Luke , Zammarchi Francesca , van Berkel Patrick H. , Marshall John F. 
Published: July 2021

Pancreatic ductal adenocarcinoma (PDAC) exhibits an extremely poor prognosis, with 5 year-survival rates &lt;5%. This is due to a lack of effective therapies for the majority of patients, 65% of whom present with metastatic disease. Integrin αvβ6 is expressed in &gt;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&lt;0.05) and decreased survival (median survival 27 vs 37.5 days, p=0.0233) relative to mice injected with αvβ6-negative TB32043 cells. When injected into the tail vein of C57BL/6 mice, αvβ6-positive TB32043mb6S2 cells exhibited significantly increased colonisation of the lungs relative to TB32043 cells (p&lt;0.0001). These data indicate that αvβ6 expression increases PDAC cell metastatic propensity. SG3299 was 17-fold more effective (p&lt;0.0001) for TB32043mb6S2 cells versus TB32043 cells in vitro, indicating αvβ6-selective killing of PDAC cells by our αvβ6-targeting PDC. Moreover, treatment of αvβ6-positive orthotopic tumors with the αvβ6-specific PDC SG3299 significantly increased survival relative to the non-targeting PDC SG3511 or saline control (median survival 48 days vs 26 days vs 25.5 days, p&lt;0.0001). When mice bearing αvβ6-positive TB32043b6S2 lung metastases generated by tail vein injection were treated with SG3299 or SG3511, the SG3299 therapy significantly reduced metastatic tumor burden relative to SG3511 (p&lt;0.05). Together, these data indicate that the peptide-drug conjugate SG3299 shows efficacy against both αvβ6-positive primary and αvβ6-positive secondary tumors in immunocompetent animals, providing a molecular-specific drug for the effective therapy of pancreatic cancer.

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.