Prostirna

Prostate cancers are the second leading cause of death by cancer in men. Hormonal ablation efficiently inhibits the growth of invasive or metastatic tumors at the initial stage of the disease. However, within a few months tumors recur and only palliative treatments are available. Over 200,000 people die every year from prostate cancer (10,000 in France). There is thus an unmet medical need for efficient treatments for castration-resistant prostate carcinomas (CRCaP). The androgen receptor (AR) is still expressed in tumors that no longer respond to hormonal ablation and is mandatory for cell survival, proliferation, and migration. Inhibition of AR synthesis by RNA interference proved in several models to inhibit the development of CRCaP. The corresponding siRNA, SXL01, was patented. The main goal of this proposal is to establish the proof of concept of the therapeutic effects of SXL01 in patients suffering from CRCaP conducting a phase I/IIA clinical trial. The proposal is innovative both in view of the target, AR in CRCaP, and the methodology used, RNA interference by systemic route. Only 3 clinical trials for siRNAs in oncology are ongoing, none in Europe and none for prostate cancers. The proposal is based on solid preclinical data which notably demonstrate - The specific antitumor effect of systemic administration of SXL01 (120µg/kg/day in saline) on CRCaP - The complete absence of stimulation of the innate immune system (TLRs, IFN, cytokines) by SXL01, even at high doses. - A preferential biodistribution of SXL01 in the prostate, a significant concentration in skin and bones, and almost none in muscles and heart. The regulatory preclinical and toxicity studies, and the clinical protocol planned for the clinical trial of SXL01 to treat CRCaP have been submitted and pre- approved by the French regulatory agency (AFSSAPS). A task in this proposal is dedicated to the development of innovative systemic drug delivery methods for siRNAs. Due to the large therapeutic applications of siRNAs, which allow targeting genes coding for proteins undrugable by antibodies or small molecular entities, the potential social and economic impact of this proposal thus extends well beyond that offered by SXL01 applications in oncology. A major problem for prostate carcinomas is their ability to metastasize. A task of this project is dedicated to assess the capacity of two patented siRNAs to inhibit tumor dissemination in response to hypoxia induced by castration or by antiangiogenic drugs. Applicants have strong and complementary assets allowing them to be at the forefront of the competition today. The proposal involves two biotech companies, SeleXel and BioAlliance Pharma, a CNRS academic group, and two medical departments from the Institut Claudius Regaud and the Hôpital Européen Georges Pompidou. This collaborative project will be determinant to develop new efficient treatments in oncology, increase the scientific knowledge, reinforce the participants’ position and strengthen their intellectual property. The results obtained would open important industrial developments and employment opportunities.