CV Science

Palma Rocchi Targeting Hsp27 Stress Induced Signaling Pathways in Castration-Resitant Prostate Cancer

Course and current status

Palma Rocchi received her PhD in 2002 from the Medicine Faculty of Marseille evaluating the molecular mechanisms involved in the androgen-independent prostate cancer. In her three years as post-doctoral fellow in the University of British Columbia Prostate Centre in Dr Gleave’s Lab. Palma Rocchi completed her formation by receiving advance training in targeting genes associated with androgen-independence and treatment resistance in Prostate cancers. She developed a drug (OGX-427, Apatorsen) using oligonucléotide antisens and siRNA approach able to significantly dose-dependent down-regulate Hsp27 protein expression level. OGX-427 has been patented and obtained an international license by the University of British Columbia and Oncogenex and clinical trials phase I and II was done in Canada and United States to evaluate the effect of OGX-427 in patients with prostate cancer and other solid tumors like breast, ovarian, bladder, prostate and lung cancer. She has now completed her post-doctoral fellowship and found a position as an independent scenior investigator in prostate cancer translational research at the French National Institute for Health and Medical Research (Inserm). She was promoted as research director in 2020 to continue working on translational research leading to improve treatment resistance in prostate cancer. Her principal research interest is focused discovery and development of RNA-targeting nanomedicine for the treatment of castration-resistant prostate cancer.

Scientific summary

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, they most ultimately become unresponsive and recur within 2 years as 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. Castration Resistant (CR) progression involves variable combinations of clonal selection, adaptive up-regulation of anti-apoptotic genes, ligand-independent androgen receptor (AR) activation, alternative growth factor pathways, and immune system 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. Previously, she identified Hsp27 as a highly over-expressed gene in CRPC. Hsp27 knockdown using antisens oligonucleotides (ASO) and siRNA increased apoptotic rates and enhanced hormone- and chemo-therapy in PC. She developed and patented a 2^nd generation ASO targeting Hsp27 (Rocchi, P., Patent PCT no 10/605, 498, 2005) that has been licensed (OGX-427, Apatorsen) and clinical trials phase I/II was done in PC. Despite OGX-427 efficiency, the functional role of stress induced Hsp27 in castration or chemotherapy-induced apoptosis remains undefined. The purpose of her work is to elucidate the pathways leading to Hsp27 action in CRPC in order to 1/ Increase the pharmacological safety of OGX-427 and 2/find new specific therapeutic targets and RNA-targeting nanomedicine for CRPC.