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Etablissement d'un nouveau modèle pérclinique de cancer de la prostate et identification de biomarqueurs de résistance au docetaxel

Abstract : One of the major hindrances in the study of the biology of prostate cancer is the limited number of laboratory models. Most of these models have been obtained from prostate tumor metastases or have been artificially established in vitro.We recently developed one new cell line (IGR-CaP1) derived from patients with clinically localized prostate cancer. In contrast to previously established models from metastases tissues, IGR-CaP1 may be a suitable model to study molecular pathways implicated in the early steps of the oncogenic development of prostate cancer. Furthermore, its high tumorigenic properties and its ability to induce mixed bone lesions, make it as a potential model for both tumor progression and drug assessment in animals.Docetaxel is the standard treatment for metastatic castration-resistant prostate cancer (CRPC) since 2004. In spite of a benefit in survival, drug resistance is often observed. Therefore, it is crucial to identify predictive markers to select patients who will respond to docetaxel. In order to investigate mechanisms of docetaxel resistance, we derived docetaxel-resistant variants from the IGR-CaP1 human prostate cancer cell line. A microarray genomic analysis comparing chemo-resistant versus sensitive prostate cell lines was used to identify a signature of genes potentially implicated in docetaxel resistance. Among these genes, we focused on LZTS1 wich is underexpressed in IGR-CaP1 resistant variants. LZTS1 is a tumor suppressor that controls the cell cycle by interacting with Cdc25C. Our data suggest that depletion of LZTS1 is potentially involved in the mecanism of docetaxel resistance. Finally, an immunohistochemical analysis will be done on human biopsies from the phase III GETUG12 trial patients. Ultimately, our study could help to improve selection of patients that could benefit from docetaxel chemotherapy.
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https://tel.archives-ouvertes.fr/tel-00739261
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Submitted on : Sunday, October 7, 2012 - 1:01:50 AM
Last modification on : Wednesday, October 14, 2020 - 4:00:39 AM
Long-term archiving on: : Tuesday, January 8, 2013 - 3:48:15 AM

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Nader Al Nakouzi. Etablissement d'un nouveau modèle pérclinique de cancer de la prostate et identification de biomarqueurs de résistance au docetaxel. Cancer. Université Paris Sud - Paris XI, 2011. Français. ⟨NNT : 2011PA11T063⟩. ⟨tel-00739261⟩

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