Transcriptional effects of CTGF inhibition and gemcitabine in the KPC mouse model of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant desmoplasia and poor tissue perfusion. These features are proposed to limit access of therapies to neoplastic cells and blunt treatment efficacy. Indeed, several agents that target the PDA microenvironment promote chemotherapy delivery and improve anti-neoplastic responses in murine models of PDA. Here, we employed the FG-3019 monoclonal antibody directed against the pleiotropic matricellular signaling molecule connective tissue growth factor (CTGF/CCN2). FG-3019 treatment increased PDA cell killing and led to a dramatic tumor response without altering gemcitabine delivery. Microarray expression profiling revealed the down-regulation by FG-3019 of several anti-apoptotic transcripts, including the master regulator Xiap, down-regulation of which has been shown to sensitize PDA to gemcitabine. Decreases in XIAP protein by FG-3019 in the presence and absence of gemcitabine were confirmed by immunoblot, while increases in XIAP protein were seen in PDA cell lines treated with recombinant CTGF. Therefore, alterations in survival cues following targeting of tumor microenvironmental factors may play an important role in treatment responses in animal models and, by extension, PDA patients.

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Neesse A, Frese KK, Bapiro TE, Nakagawa T, Sternlicht MD, Seeley TW, Pilarsky C, Jodrell DI, Spong SM, Tuveson DA