A nutlin has on-target activity in liposarcomas, which commonly harbor MDM2 amplifications.
Major finding: A nutlin has on-target activity in liposarcomas, which commonly harbor MDM2 amplifications.
Approach: A proof-of-mechanism neoadjuvant study assessed markers of p53 activation in tumor biopsies.
Impact: Further study of the efficacy of small-molecule MDM2 antagonists in liposarcoma is warranted.
Liposarcoma, the most common adult soft-tissue sarcoma, is generally managed by surgery, but unresectable or relapsed liposarcomas are highly chemoresistant. Amplification of MDM2, which encodes a negative regulator of p53, is a hallmark of well-differentiated and dedifferentiated liposarcomas, suggesting that targeted inhibition of MDM2 may be effective in these tumors. Nutlins are potent, selective inhibitors of MDM2–p53 binding that restore p53 activity and inhibit tumor growth in preclinical studies. Ray-Coquard and colleagues conducted an exploratory study to evaluate the nutlin RG7112 in a neoadjuvant setting in liposarcomas. Twenty patients received RG7112 for up to 3 cycles before surgery, and tumor biopsies were collected before treatment initiation, during cycle 1, and at resection. The primary endpoint was to evaluate biomarkers of p53 reactivation, and secondary endpoints included safety and antitumor activity. During treatment, significant increases in levels of both p53 and p53 targets were observed compared with baseline levels. A significant decrease in proliferative activity and a trend toward increased apoptosis further suggested that p53 reactivation led to cell-cycle arrest and cell death. However, at resection, the biomarker levels did not significantly differ from those at baseline, indicating that the pharmacodynamic response was reversible upon discontinuation of treatment. Every patient experienced at least 1 adverse event, and 8 patients had serious hematologic adverse events, though all recovered. One patient had a partial response, and stable disease was observed in 14 patients, though it is unclear whether disease stabilization occurred in these patients due to p53 reactivation or because of the slow-growing nature of liposarcomas. Although this exploratory study was small and adverse effects of RG7112 will need to be closely monitored, these findings suggest that nutlins can have on-target activity and support the further evaluation of these compounds in liposarcoma.
Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012 Oct 17 [Epub ahead of print].