SENESCENCE THERAPY · "PRO –SENESCENCE” THERAPY IN PEDIATRIC BRAIN TUMORS""

'Pro-senescence' therapy in pediatric brain tumours

Cellular senescence, an irreversible cell growth arrest, is an intrinsic tumour suppressor mechanism which opposes tumourigenesis in vivo. We have recently discovered a novel type of cellular senescence response that can be elicited by acute loss of the tumour suppressor phosphatase and tensin homologue (PTEN) one of the main tumours suppress genes altered in cancer. While subtle reduction of PTEN levels promote tumour initiation and progression, we have recently demonstrated that complete inactivation of PTEN drives senescence even in arrested cells in absence of hyper-replication and a deoxyribonucleic acid (DNA) damage response. We have named this novel senescence response; PTEN-loss-induced cellular senescence (PICS). Importantly, we have demonstrated that this senescence response depends on the functional activity of mammalian target of rapamycin (mTOR) mediated p53 translation. Therefore, loss of the tumour suppressor p53 promotes senescence evasion, tumour invasion and cancer progression. Importantly, we have recently demonstrated that PTEN pharmacological inhibition drives senescence and tumour growth arrest in vivo, in a prostate cancer xenograft model. Medulloblastoma (M) and neuroblastoma (N) are two main intra- and extra-cranial paediatric tumours. While these tumours are usually associated with alteration of the proto-oncogenes c- myc and n-myc, they retain a normal PTEN and p53 status. Therefore, these represent an ideal model system to test the efficacy of novel 'pro-senescence' compounds either alone or in combination. The primary aim of this Marie Curie project is to demonstrate the efficacy of the novel PTEN inhibitor, VO-OHpic, in this model system. Secondary aim of this project is to test the potential synergy between VO-OHpic and the compounds that can stabilize p53 such as the MDM-2 inhibitor, Nutlin-3, and different DNA damage agents (i.e. X-radiation). Giving the current effort in identifying novel non-cytotoxic compounds for the treatments of paediatric tumours our project has provide additional therapeutics options to the cure of these frequent paediatric tumours.

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