Targeting p53 Tumor Suppressor for AML Therapy

The p53 tumor suppressor gene is mutated in over half of human solid cancers. However, in hematological malignancies the frequency of p53 mutation is relatively low, and the majority of tumors express a wild-type, transcriptionally competent protein. Nevertheless, leukemia cells have abnormalities in p53 regulatory proteins (e.g., MDM2 or MDMX overexpression, CDKN2A/ARF deletion, and ATM inactivation), frequently resulting in inactivation of the p53 pathway. Unleashing the powerful antitumor activity of the tumor suppressor by nongenotoxic pharmacological intervention in p53 regulation has been considered an attractive strategy. Recently, p53-targeted therapies have been developed with the potential to significantly impact cancer therapy. RG7112 and APR-246 have been tested in phase I trials in patients with hematologic malignancies. RG7112, a new member of the Nutlin family of MDM2 antagonists, prevents wild-type p53 from binding to its negative regulator MDM2, leading to p53 stabilization and activation. PRIMA-1 derivative APR-246 restores wild-type function in cells with mutant p53. The accumulated knowledge about p53 function and its regulation, combined with the advances in drug discovery technologies should translate into novel p53-based therapeutics in the clinical management of leukemia.