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Cancer is among the leading causes of morbidity and mortality worldwide. The efficacy of the available anticancer chemotherapy remains quite limited and generally associated with increasing drug resistance and severe side effects. The discovery of new anticancer agents is, therefore, a major medical priority. The p53, p63 and p73 tumor suppressors are key therapeutic targets in cancer. Inactivation of these p53 family proteins by interaction with MDM2 and MDMX, and mutation of p53 are common events in human tumors, leading to two major anticancer therapeutic strategies: inhibition of the MDMs interaction with p53 family proteins, and mutant (mut) p53 reactivation. To date, most of the pharmacological efforts have been focused on the p53-MDM2 interaction, with only one small molecule inhibitor of p53-MDMX interaction and three p53-MDM2/MDMX dual interaction inhibitors reported. Inhibitors of p63/p73-MDMs interaction are still mostly unknown. The identification of reactivators of mut p53 brought new expectations to the therapy of tumors expressing mut p53. Moreover, the discovery of mut p53 oncogenic gain-of-function (GOF), mainly through interaction with transcriptionally active p53 family proteins, led to a new promising anticancer strategy.
In previous works, we developed innovative targeted screening assays, combining yeast and human tumor cells, which led to the identification of hit small molecule activators of p53 family proteins.
With this proposal, we aim at fully developing the potentials of our approach and recent results. Particularly, we intend to:
1. Gain knowledge into mut p53 biology in the context of its gof
2. Develop anticancer drug candidates activators of p53 family proteins
3. Design effective combination therapies with conventional chemotherapeutic drugs
4. Develop a targeted drug delivery nanosystem for efficient and selective delivery of our drug candidates into tumor cells
5. Validate the antitumor properties of our anticancer drug candidates in genetically-characterized patient-derived xenograft (pdx) models
Collectively, relevant advances in anticancer therapy are expected to emerge from this project.
