Targeting MDM2 overexpression is therefore an attractive potential strategy for p53 reactivation, especially in hematological malignancies — a strategy that is now undergoing early development against AML, multiple myeloma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL).1,3,10-12

Several approaches to MDM2 inhibition or mitigating MDM2’s impact on p53 are being explored around the world, including engineered p53-mimicking peptides and small-molecule agents that can block the MDM2/p53 interface, such as piperidinone, spirooxindoles, and nutlins.1,12

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Preclinical research suggests that when tumors harbor wild-type TP53 — and possibly, mouse studies suggest, even in those harboring some type of TP53 mutation — the small molecule MDM2 antagonist, nutlin-3, can rapidly reactivate the p53 pathway and restore p53 levels, inducing apoptosis.13

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Nutlin-3a was first developed more than a decade ago, in 2004, by Hoffman la Roche.1 Nutlin-3 exhibits anti-myeloma activity in wildtype TP53, and preclinical studies suggest possible synergy against myeloma when combined with bortezomib, melphalan, or etoposide.12,14 Researchers in Canada reported that in multiple myeloma cell lines and primary myeloma samples, adding nutlin therapy to bortezomib reduced cell proliferation and viability in myeloma cells with unmutated p53, for example.14

“Nutlin plus [bortezomib] showed a synergistic anti-myeloma activity as evidenced by a significant increase of cytotoxicity with respect to each agonist alone,” reported senior study author Hong Chang, MD, PhD, FRCPDC, of the Toronto General Hospital Institute in Canada, and coauthors.15 “These effects were accompanied by accumulation and induction of proapoptotic targets, PUMA, BAX, and BAK.”

Because p53 inactivation is a mechanism of tumor resistance to tyrosine kinase inhibitors (TKIs), similar research is under way to explore nutlin-3’s potential in combination with imatinib against Philadelphia chromosome–positive ALL; early in-vitro cell line findings suggest possible synergy between imatinib and nutlin-3 plus tanshinone IIA.15