Liposarcoma is a rare but highly recurrent soft tissue neoplasm. Combination of surgery and radiotherapy is the main treatment for liposarcoma patients while chemotherapy remains experimental and limited depends on disease subtypes. Well-differentiated and dedifferentiated liposarcoma (WDLPS/DDLPS) represents ~50% of all diagnosed liposarcoma and their benefit from chemotherapy has been documented to be minimal. Concomitant amplifications of MDM2 and CDK4 are frequently found in WDLPS/DDLPS patients, suggesting that the combination with two targeted agents may worth further development for the treatment. APG-115 is a potent, selective, orally bioavailable small molecule inhibitor of MDM2-p53 protein-protein interaction and thus activates tumor suppression activity of p53 in p53 wild-type tumors. Currently, APG-115 is in clinical development as a single agent or in combination with PD-1 blockade immunotherapy for solid tumors, including sarcoma. To further explore the sensitive patient population and predictive biomarkers for APG-115, in this study, we evaluated the effect of the combined MDM2/CDK4 inhibition in p53 wild-type, MDM2 and CDK4 amplified liposarcoma using a preclinical xenograft tumor model derived from a dedifferentiated liposarcoma patient (PDX). Tumor-bearing mice were treated with MDM2 inhibitor APG-115, CDK4 inhibitors palbociclib/ribociclib, or their combinations. In the first experiment, APG-115 administered at 40 mg/kg as a single agent demonstrated antitumor activity in the DDLPS PDX model. In comparison with the single agents, the combination treatment with APG-115 and palbociclib or APG-115 and ribociclib exerted synergistic antitumor effects, resulting in T/C values of 16.9% and 27.1%, respectively (T/C value, average tumor volumes in treatment group vs. the vehicle control group). Partial tumor regression (PR) was achieved in 1/5 animals in both combination treatment groups but not in single arms. Another independent experiment with a higher dose of APG-115 (80 mg/kg) combined with palbociclib showed further improved antitumor activity with T/C value of 7.0% (2/5 PR). Collectively, our results suggest that the combination therapy of APG-115 and a CDK4 inhibitor may benefit WDLPS/DDLPS patients with p53 wild-type, and MDM2 and CDK4 amplifications clinically.

Citation Format: Douglas D. Fang, Guoqin Zhai, Chunhua Xu, Qingyang Gu, Jingwen Wang, Saijie Zhu, Dajun Yang, Yifan Zhai. MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1253.