Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts

Abstract

Pancreatic ductal adenocarcinoma (PDA) shows a rich stroma where cancer-associated fibroblasts (CAFs) represent the major cell type. CAFs are master secretors of proteins with pro-tumor features. CAF targeting remains a promising challenge for PDA, a devastating disease where treatments focusing on cancer cells have failed. We previously introduced a novel pharmacological CAF-targeting approach using the somatostatin analog SOM230 (pasireotide) that inhibits protein synthesis in CAFs, and subsequent chemoprotective features of CAF secretome. Using primary cultures of CAF isolated from human PDA resections, we here report that CAF secretome stimulates in vitro cancer cell survival, migration and invasive features, that are abolished when CAFs are treated with SOM230. Mechanistically, SOM230 inhibitory effect on CAFs depends on the somatostatin receptor subtype sst1 expressed in CAFs but not in non-activated pancreatic fibroblasts, and on protein synthesis shutdown through eiF4E-Binding Protein-1 (4E-BP1) expression decrease. We identify interleukin-6 as a SOM230-inhibited CAF-secreted effector, which stimulates cancer cell features through phosphoinositide 3-kinase activation. In vivo, mice orthotopically co-xenografted with the human pancreatic cancer MiaPaCa-2 cells and CAFs develop pancreatic tumors, on which SOM230 treatment does not inhibit growth but abrogates metastasis. Consistently, CAF secretome stimulates epithelial-to-mesenchymal transition in cancer cells, which is reversed upon CAF treatment with SOM230. Our results highlight a novel promising anti-metastatic potential for SOM230 indirectly targeting pancreatic cancer cell invasion through pharmacological inhibition of stromal CAFs.

Does pasireotide directly modulate skeletal muscle metabolism?

“…This finding, although in contrast with the effect of highdose pasireotide in increasing protein synthesis reported in this study, is in line with the previously demonstrated role of SSAs in the inhibition of mTOR and its effectors p70/ S6K and 4E-BP1 in different cell models [6,8]. Therefore, as suggested by the Authors, the Akt-mTOR pathway does not seem to be involved in the pasireotide-mediated anabolic effects, and other signaling cascades could mediate this drug-related activity.…”

“…However, despite the initial search for a compound able to closely mimicking native somatostatin (SRIF-14), preclinical studies have demonstrated that this compound shows different functional properties compared to both native somatostatin-14 and first-generation somatostatin analogs (SSA) (e.g., octreotide) [4]. In this context, due to the peculiar pharmacological characteristics of pasireotide, a number of studies investigated its potential role on extra-pituitary cell types and tissues [5,6].…”

“…Noteworthy, a number of preclinical studies already demonstrated that pasireotide is able to activate a number of different effectors in normal and tumor cells, modulating cell functions in both a direct and indirect way. For example, pasireotide has been shown to exert its anti-proliferative effect via either the downregulation of MAP kinase pathway, or the inhibition of growth or angiogenic factors [6,8,9].…”

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…The human orthologue SAA1 was overexpressed in CAFs of patients with PDA and correlated with worse prognosis indicating a potential novel therapeutic target 81. Another interesting study from Bousquet and colleagues in Toulouse recently showed that selective pharmacological activation of somatostatin receptors in CAFs blocks the mTOR/4E-BP1 pathway and subsequent synthesis of several CAF-derived secreted proteins,82 including IL-6 that resulted in sensitisation to gemcitabine and inhibition of cancer cell metastasis 90…”

Pasireotide in the treatment of neuroendocrine tumors: a review of the literature

“…In several tumors, stromal cancer-associated fibroblasts (CAF) have a main role in cancer progression and in the development of chemoresistance via the secretion of growth factors and immune suppressive cytokines, mesenchymal-epithelial cell interactions and generation of specific niches within the tumor microenvironment that facilitate the acquisition of drug resistance (Wang et al 2017). In pancreatic adenocarcinoma, pasireotide showed a significant antitumor activity through an effect on CAF (Moatassim-Billah et al 2016). Exclusively, pasireotide, and not octreotide, was able to inhibit in vitro CAF tumorigenic features.…”