Abstract 2536: Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) cell lines

Abstract

Abstract Background: Malignant Peripheral Neural Sheath Tumors (MPNST) are a type of sarcoma that arise spontaneously from a peripheral nerve or plexiform neurofibroma. Approximately 1 in 10 people with a constitutional mutation in the NF1 gene, a negative regulator of RAS function, develop MPNST with a peak incidence in the adolescent and young adult years. Available chemotherapy treatment for MPNST has low response rates, and the prognosis for unresectable or metastatic tumors is poor. A clinically relevant system to rapidly evaluate the efficacy of many agents and combinations of agents on MPNSTs which can be translated into clinical trials is needed. Methods: Here, we seek to identify promising single drug and combination therapies using FDA approved and other agents of interest via high-throughput screening platforms, based on established MPNST cell line models (SNF02.2, SNF10.1, SNF94.3, and SNF96.2). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds and combinations at clinically-relevant concentrations and exposure times that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results. Fifty-four agents with roughly ¼ inhibitors of the RAS downstream pathways, another ¼ kinase inhibitors, and the remainder a representation of many classes of agents with diverse mechanisms of action were screened across 4 cell lines with biological replicates. The majority of the agents are FDA approved. Others are in active clinical trials, demonstrate a promising mechanism of action, or have published preclinical data in MPNST models. CellTiter Glo assays were used to assess cell viability at the maximal achievable serum concentration from phase I studies and at two lower concentrations. Promising agents were then studied in two-drug combinations to evaluate for synergy in addition to efficacy of the combination. The combinations were selected with careful attention to known drug-drug interactions, metabolism, schedule and non-overlapping toxicities. Results: Our screening results indicate that a number of FDA approved chemotherapy agents, evaluated at clinically relevant concentrations and exposure times, significantly reduced cell viability across all cell lines tested. These findings suggest promising opportunities for developing combination clinical trials. Citation Format: Elliott Kahen, Diana Yu, Christopher Cubitt, Dan Sullivan, Damon R. Reed. Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2536. doi:10.1158/1538-7445.AM2015-2536