Pharmacological reactivation of p53 for cancer therapy

Orateur : Galina SELIVANOVA (Karolinska Institute, Stockholm, Sweden)

p53 is a key tumor suppressor, inactivated in the majority of human cancers. Reconstitution of p53 function leads to regression of aggressive tumors in vivo, which inspires the idea to combat cancer by small molecules reactivating p53 in tumors. We have identified a small molecule PRIMA-1 which restores the active conformation and function of different p53 mutants in tumor cells of different origin and suppresses the growth of human xenograft tumors in mice. Since around 50% of all human tumors carry mutations in p53, mutant p53- reactivating compound could be widely applicable for cancer therapy. PRIMA-1 derivative APR-246 is currently being tested in Phase II clinical trial in ovarian cancer patients. p53 can induce diverse responses ranging from cell death to growth arrest and DNA repair, which might affect the outcome upon application of p53-reactivating drugs in clinic. Elucidation of the molecular mechanisms defining the biological response upon p53 activation remains a grand challenge in the p53 field. To understand the mechanisms of cell fate decisions by p53 we apply high throughput techniques, such as ChIP-seq, transcriptomic and proteomic analyses. It has been recently shown in mouse models that p53 unable to induce its major cell cycle arrest and apoptosis targets still acts as a tumor suppressor, highlighting the importance of its other, non-canonical functions. We found that p53 loss leads to gross changes in the epigenetic state of human fibroblasts which resemble those found in breast tumors. This finding suggest a novel facet of p53-mediated tumor suppression.

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