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. Although arrested, senescent tumor cells remain metabolically active and secrete a variety of cytokines and inflammatory factors known as the senescence-associated secretory phenotype (SASP). The SASP of tumor cells can activate the tumor immune response and promote the clearance of senescent tumor cells, a phenomenon referred as senescence surveillance. However in tumors where senescence surveillance is evaded, senescent tumor cells persist in the tumors and trough the SASP increase angiogenesis, cell migration, invasion and even metastasis. Therefore removal of senescent cells (senolytic therapy) has been proposed as a strategy to improve the efficacy of currently available treatments. Nowadays there are few examples of effective senolytic compounds. The majority of these compounds target Bcl-2, a regulator of apoptosis that is found increased in senescent cells. However the efficacy of these compounds is variable and it depends by the genetic background of the senescent tumor cells being effective in certain type of senesce response but not in others (see also Task 1). The main objective of this application is to identify novel senolytic therapies that eliminate Pten null senescent tumor cells. We aim to achieve this objective by: 1) screening compounds libraries already available in the lab, 2) Identify immunotherapies that harness the tumor immune response against senescent tumor cells thereby promoting their clearance. We have recently found that tumor infiltrating myeloid cells can hinder senescence surveillance by inhibiting the proliferation and function of T cells and that compounds that block the recruitment of these cells in the tumors can activate tumor immune clearance in prostate tumors treated with chemotherapy. Therefore, a better characterization of the tumor secretome and the immune subsets infiltrating senescent tumors may identify novel entry-points for cancer therapy.