Identifying drug therapies for plexiform neurofibromas in Neurofibromatosis Type 1 through chemo-genomic analysis (P3.145)

Objective: Characterize the genomic and transcriptomic profile of a panel of human tumor-derived pNF cell lines to explore how genetic background interacts with drug response in NF1 plexiform neurofibormas. Background: Plexiform neurofibromas (pNFs) impact ~40% of people with Neurofibromatosis Type 1 (NF1), a common neurogenetic syndrome resulting in tumors throughout the nervous system. pNF may cause disfigurement, neurologic morbidity and malignant transformation to sarcoma. As there are no standard therapies for these tumors, there is an urgent need for new therapeutic agents. Design/Methods: Six human pNF cell lines ( NF1 +/+ ; NF1 +/− ; NF1 −/− ) underwent molecular characterization via Exome-Seq, RNA-Seq, and DNA copy-number evaluation including assessment of genes differentially expressed between NF1 +/+ ; NF1 +/− ; and NF1 −/− cells. The cells also went through high-throughput screening with a library of 1912 oncology compounds encompassing different phases of development. Dose-response curves from the screen were used to derive potency and efficacy metrics for each drug and each cell tested. Area under the curve (AUC) was calculated from both the fitted curve and raw data points as well as the % activity at the maximum concentration (MAXR) and the log AC 50 value. Results: Primary and immortalized cell lines had consistent NF1 mutational status, but primary NF1 −/− cells exhibit lower expression of NF1 compared to NF1 +/+ or NF1 +/− cells and overall NF1 expression was lower in immortalized than primary cells. There were 390 differentially expressed transcripts (q NF1 −/− versus NF1 +/+ or NF1 +/− cells, of which 294 encode transcripts. The preliminary drug screen result was notable for drugs inhibiting BTK, HSP90, and MAP2K1 targets having stronger efficacy in the NF1 −/− cells. Conclusions: Human pNF derived immortalized cells have been fully characterized as a tool to support development of new therapeutics for pNF. Early drug screen results reveal an interaction between molecular characteristics and drug sensitivity that support molecularly driven drug discovery for these tumors. Study Supported by: Neurofibromatosis Therapeutic Acceleration Program National Center for Advancing Translational Science Disclosure: Dr. Blakeley has received personal compensation for activities with Abbvie, Inc. Dr. Blakeley has received research support from GlaxoSmithKline. Dr. Gosline has nothing to disclose. Dr. Stathis has nothing to disclose. Dr. Guha has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Thomas has nothing to disclose. Dr. Verma has received personal compensation for activities with GSK as an employee. Dr. Guinney has nothing to disclose. Dr. Wallace has nothing to disclose. Dr. Ferrer has nothing to disclose.