Endocrine Abstracts

Pancreatic ductal adenocarcinoma (PDA) remains a highly lethal malignancy. Therapeutic strategies aimed at targeting pancreatic cancer cells have failed. We hypothesized that such pitfall is due to the functional heterogeneity of this tumor which comprises both cancer and stromal cells. It is now recognized that cancer-induced but host-derived stromal events support tumor growth and chemoresistance. In order to reach efficacy with chemotherapies, we believe that stroma has to be co-targeted.

Cancer-associated fibroblasts (CAFs) are the most abundant cells present in PDA stroma. We showed that human activated (αSMA-expressing) pancreatic CAFs (primary cultures isolated from human tumor resections) express the somatostatin receptor subtype sst1, but not the other receptor subtypes (sst2-sst5), by opposition to non-activated (αSMA-negative) pancreatic fibroblasts (PaSC, pancreatic stellate cells isolated from normal pancreas) which do not express any sst. This was confirmed by immunohistochemistry on human PDA.

Somatostatin receptors are known to be highly expressed in neuroendocrine tumor cells where they are used in clinic as therapeutic targets for their antisecretory and antitumoral role. However, these receptors are not expressed in pancreatic cancer cells (PDA). Data regarding the expression of somatostatin receptors in the tumor stroma are quasi-inexistent.

Interestingly, we observed a hyperactivation of the PI3K-mTORC1 pathway in CAFs as compared to PaSC, which was blunted by the somatostatin analog SOM230 (pasireotide) through activation of sst1, but not by octreotide. The observed elevated protein synthesis rates in CAFs were also dramatically decreased by SOM230 treatment, resulting in the inhibition of soluble and extracellular matrix protein secretion. Chemoprotection provided by CAF secretome on cancer cells was blunted by SOM230 treatment, involving interleukin-6 the expression of which was decreased by SOM230 specifically at the protein, but not mRNA, level. In vivo, athymic mice orthotopically co-xenografted with the human pancreatic cancer cells and CAFs developed tumors, the growth of which was dramatically reduced upon mouse treatment with the combination SOM230+gemcitabine (chemotherapy of reference for PDA), but not by each single drug. Interestingly also, we showed that 60% of untreated, and 100% of gemcitabine-treated mice, developed metastases (lungs and liver), whereas none of the SOM230-treated or SOM230+gemcitabine-treated mice showed any metastases. This is consistent with the ability of CAF conditioned media to induce epithelial-to-mesenchymal transition in pancreatic cancer cells (decrease or increase of E-cadherin or N-cadherin expression, respectively, and increase of expression of the EMT Zeb1, Snail & Slug transcription factors), which is reverted with conditioned media from SOM230-treated CAFs.

Our results highlight a novel promising anti-tumor activity for SOM230 indirectly targeting pancreatic cancer cell chemoresistance, invasion and metastasis through pharmacological inhibition of stromal CAFs.