Deregulated ERK signaling in MPNST. ERK signaling output is activated in many human tumors, including those with BRAF and RAS mutations and those with loss of NF1. Several pediatric solid tumors are known to express these mutations, including a subset of rhabdomyosarcoma, neuroblastoma, and MPNST. Our research aims to investigate whether MEK inhibition may effectively inhibit ERK output in pediatric sarcomas with activation of ERK signaling. A primary focus of this work is determining the biochemical and adaptive signaling response to MEK inhibition and other targeted therapies in models of MPNST, to identify mechanisms by which tumors with loss of NF1 can evade MEK inhibition, and to identify targets for more effective and combination therapy.
De novo and acquired resistance to RAF/MEK targeted therapy in BRAF mutant high grade gliomas. While molecularly targeted therapies are being explored in high-grade gliomas, they have had limited success to date. BRAF V600E mutations in primary brain tumors represent an exciting and promising new opportunity to apply targeted therapeutic approaches if barriers to their success, including de novo and acquired resistance, can be overcome. This project involves characterization of the limits of RAF/MEK targeted therapy in BRAF mutant brain tumors, by sequencing pre- and post-treatment pairs. Our goal is to identify mechanisms of acquired resistance to therapy. We recently published the first report of a mechanistically-validated novel resistance mutation, identified in a pediatric brain tumor patient treated with dabrafenib (Wang et al. Cancer Discovery, 2018).
Effects of farnesyl transferase inhibition in pediatric solid tumors with oncogenic mutations in HRAS. Despite the lack of clinical efficacy seen with farnesyl transferase inhibition in previous pediatric clinical trials, the FTI tipifarnib has now demonstrated preliminary activity when given to a genomically selected population of head/ neck squamous cell carcinoma (HNSCC) patients. Based upon this, we hypothesize that farnesyl transferase inhibition will demonstrate clinical activity when given to pediatric patients whose tumors harbor oncogenic mutations in HRAS. We are now studying the preclinical effects of tipifarnib in models of RAS mutated rhabdomyosarcoma, to determine whether FTI has isoform specific activity in RMS and other pediatric solid tumors.