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Ciblage pharmacologique du microenvironnement de l'adénocarcinome canalaire pancréatique

Abstract : Pancreatic ductal adenocarcinoma (PDAC) correlate with a poor prognosis, because of its late diagnosis, its aggressiveness, and its propensity to metastasize quickly. New therapeutic strategies are urgently needed to improve this prognosis. One of these strategies is to target PDAC microenvironment, which is very dense and active and represents a large part of the tumor mass. It is composed of an extracellular matrix, endothelial cells, immune cells and cancer-associated fibroblasts (CAFs). Through physical and chemical relations, the microenvironment, and particularly CAFs and their secretions, promotes tumor progression at in the primary tumor and at metastatic sites. Our team has demonstrated an antitumor effect of a somatostatin analog, pasireotide or SOM230. Somatostatin is a hormone that inhibits many biological functions, including endocrine and exocrine secretions and cell proliferation, and with an anti-tumor effect demonstrated in different types of cancer. Via the receptor sst1 expressed by CAFs, pasireotide is able to block CAFs secretions, and thus restore pancreatic cancer cells sensitivity to chemotherapy and slow down tumor growth. The aim of my PhD consisted in demonstrating the efficacy of the combination of gemcitabine, the reference chemotherapy in PDAC, and the somatostatin analog SOM230 in mouse models faithfully mimicking the physiopathology of human PDAC. My results show a major effect of the combination of treatments on the development of metastases, both on orthotopic co-graft models and on the KPC genetic model. This effect is associated with a reduction in the recruitment of pro-tumor immune populations, particularly tumor-associated macrophages and MDSCs. We identified the macrophage growth factor CSF-1 as a key protein implicated in the immunomodulatory effect of CAFs, and its secretion is strongly reduced by the SOM230 treatment. Considering recent failures with treatment that aimed to suppress CAFs, target their secretions seems to be a more promising strategy in the treatment of PDAC.
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Rémi Samain. Ciblage pharmacologique du microenvironnement de l'adénocarcinome canalaire pancréatique. Médecine humaine et pathologie. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30326⟩. ⟨tel-02475960⟩

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