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Manipulation of senescence pathways for cancer therapy: from experimental models to clinic

Final Report Summary - PICS THERAPY (Manipulation of senescence pathways for cancer therapy: from experimental models to clinic)

The overall goal of the project was to develop a screening platform for the identification of novel compounds that increase senescence in cancer cells without affecting normal cells. Senescence is an irreversible cell growth arrest that occurs in all the cells of the human body during aging. However, senescence can also occur in cancer cells upon over-expression of oncogenes, loss of tumor suppressor genes or cytotoxic treatments (e.g chemotherapy, radiotherapy). PTEN is one of the major tumor suppressor genes lost or mutated in severaltype of cancers. By characterizing the genes regulators of this response, we have previously shown that compounds that target some of these genes enhance PICS and can be used for cancer therapy (Alimonti, JCI 2010). However, the use of these inhibitors in the clinic has been limited by their poor tolerability in cancer patients (Nardella, Nat Rev Cancer 2011). Identification of novel “druggable” targets that regulate senescence in PTEN null tumors would help in developing pro-senescence compounds for the treatment of different types of cancer. The main objective of this proposal was to identify novel effective and cancer cell-selective selective “pro-senescence” compounds. We have therefore set up a screening platform and identified several small molecule inhibitors that enhance senescence in PTEN null tumor cells without affecting normal cells. We have moved to the level of pre-clinical trials two of these inhibitors demonstrating the efficacy of these compounds in vivo and their tolerability in animal models. Given the known interplay existing between senescence cells and tumor immune response, an additional objective of this ERC grant was to characterize in vivo the senescence-associated secretory phenotype (SASP) of PICS and to study in vivo the effect of the PICS SASP on the tumor microenvironment and tumor immune response. We have completed the characterization of the SASP of PICS and we have found that treatments that reprogram the SASP of PICS can activate the tumor immune response enhancing the clearance of senescence tumor cells. Finally, we have characterized the immune landscape of Pten deficient prostate cancers and found that tumor-infiltrating myeloid cells can antagonize pro-senescence therapies. By blocking the tumors recruitment of these cells we have also demonstrated that the efficacy of pro-senescence therapy can be enhanced. These findings have provided us with the rationale to test the efficacy of immunotherapies that enhance the clearance of senescence tumor cells in combination with pro-senescence compounds at the clinical level. A clinical trial validating this hypothesis is currently ongoing.