Comprendre les voies de signalisation induites par le stress Hsp27 menant la résistance au traitement du cancer de la prostate : développement nanothérapeutique

Prostate cancer (PC) represents one of the most common cancers in industrialized countries. Patients with localized disease may be treated with surgery or radiation, while androgen ablation is used as first-line therapy in patients with metastatic disease. While most patients initially respond well to this hormonal therapy, most of them become unresponsive and recur within 2 years with castration-resistant prostate cancer (CRPC). Recently, docetaxel-based regimens have demonstrated improved survival in men with CRPC in two different, large, phase III studies. However, the median overall survival was prolonged for only ~2-3 months. Recently, cabazytaxel and Abiraterone has been approved as second line chemotherapy but overall survival is only around 12 to 18 months. The actual therapeutic strategy to delay or prevent the emergence of the treatment-refractory phenotype in advanced PC involves targeting genes activated by androgen withdrawal. Castration Resistant (CR) progression involves variable combinations of clonal selection, ligand-independent androgen receptor (AR) activation and alternative growth factor pathways and adaptive up-regulation of anti-apoptotic genes and immune escape. Additional therapeutic strategies targeting molecular mechanisms mediating resistance, combined with immunotherapy must be developed. One strategy to improve therapies in advanced PC involves targeting genes that are activated by androgen withdrawal, either to delay or prevent the emergence of the CR phenotype. During my post doc at the Prostate Centre (Vancouver, Canada), I identified Hsp27 as a highly over-expressed gene in CRPC. Hsp27 knockdown using antisense oligonucleotides (ASO) and small interference RNA (siRNA) increased apoptotic rates and enhanced hormone- and chemo-therapy in PC. I developed and patented a 2nd generation ASO targeting Hsp27 (Patent PCT no 10/605, 498, 2005)1 that has been licensed (OGX-427, Apatorsen) by Oncogenex and clinical trials phase I/II was performed in process in prostate, bladder, lung and pancreatic cancers.

Despite OGX-427 efficiency, the functional role of stress-induced Hsp27 in castration or chemotherapy-induced apoptosis remains undefined. The purpose of my work since my CR1 recruitment at Inserm (Octobre 2007) is to elucidate the pathways leading to Hsp27 action in CRPC in order to 1/ Increase pharmacological safety of Hsp27 inhibition 2/find new specific therapeutic targets and nanotreatment strategies for CRPC that would have no toxicity for normal tissues.