Excellence Grant –Development of senolytic therapies for chemotherapy-treated prostate cancer
Prostate cancer is the second commonest malignancy in men worldwide and the second commonest cause of male mortality. Patients with metastatic prostate cancer, specifically those with disease progression following primary androgen ablation therapy and addition or withdrawal of an anti-androgen, are generally considered to be refractory to hormonal therapy. The treatment of castration-resistant prostate cancer (CRPC) remains unsatisfactory. Unfortunately, chemotherapy can only marginally improve patient survival, providing a palliative benefit in this setting. Patients with hormone-refractory prostate cancer have, thus far, not been cured with either hormonal treatments or chemotherapy. It is hoped that the development of novel targeted therapies and immunotherapies will improve the outcome of patients with androgen refractory diseases. PTEN is one of the most frequently altered tumor suppressor genes in prostate tumors and PTEN loss is often associated to both chemo and radiotherapy resistance in prostate cancer patients. Despite the high incidence of PTEN mutations or deletions a treatment that target prostate tumors harboring PTEN alterations still does not exist. Major objective of this proposal is to identify novel treatment modalities for the therapy of PTEN deficient prostate cancer. Cellular senescence is a stable cell growth arrest that occurs in tumor cells subjected to different stress including treatment with chemo-radiotherapy or targeted therapies. Several findings in vivo demonstrate that senescence limits tumor progression.