Abstract 4199: Developing therapies for rare tumors: Using mouse models of malignant peripheral nerve sheath tumors to complement rare human samples in drug screens

Abstract

Abstract Rare cancers are defined by the US Orphan Drug Act as affecting <200,000 patients in the US. For patients with these cancers, there may be an urgent need for new therapies; however, these rare cancers present challenges to drug development. Because of the small number of patients, the cancers are not well characterized, the molecular mechanisms may not be well-understood, and there may not be adequate model systems available for research and drug development. The Rare Tumors Initiative in the Intramural Research Program at the National Cancer Institute is focusing on overcoming hurdles in rare tumor research by developing new approaches to treat malignant peripheral nerve sheath tumors (MPNST). MPNSTs occur in younger adults with an incidence of 1 in 100,000, with a higher incidence in patients with Neurofibromatosis type 1. Due to a limited number of high quality human MPNST tumor lines, drug testing has been challenging both in vitro and in vivo. A genetically engineered mouse model carrying mutations in Nf1 and Trp53 develops MPNST spontaneously starting around 3 months of age. We have generated tumor lines from over 30 independent mouse MPNSTs, from different sexes and genetic backgrounds that we are using to test drugs in combination with available human MPNST lines. We find good concordance between the mouse and human MPNST lines in response to drugs. Furthermore, although the MPNST lines show good dose response and high maximum response to many targeted compounds, the concentrations of drug required to achieve inhibition is often high, suggesting that one of the difficulties in developing MPNST therapy is the inherent resistance of MPNST cells to drug inhibition. We will present results of ongoing drug screens in panels of mouse and human MPNST cell lines, using drugs that are in different phases of clinical trials or approved for other diseases. Citation Format: Karlyne M. Reilly, Robert G. Tuskan, Brigitte C. Widemann. Developing therapies for rare tumors: Using mouse models of malignant peripheral nerve sheath tumors to complement rare human samples in drug screens. [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 4199. doi:10.1158/1538-7445.AM2015-4199