PROJECT SUMMARY/ABSTRACT This supplement support is for Dorea Jenkins in the lab of Steven Carroll, an African-American postdoctoral scholar at the Medical University of South Carolina. Her goal is to become an independent researcher. Our R01 focuses on therapies to treat malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive neoplasms that occur in patients with neurofibromatosis type 1 (NF1) and sporadically in the general population. The prognosis for patients with an MPNST is grim as current therapeutics are ineffective. Ras hyperactivation, results from loss of NF1 that encodes the tumor suppressor, neurofibromin. This suggests that inhibiting Ras signaling would be an effective means of treating MPNSTs. Ras is difficult to directly target and drugs targeting Ras signaling is not effective in patients with MPNSTs. Therefore, we investigate therapeutically targeting key upstream activators of Ras, receptor tyrosine kinases (RTKs) in MPNSTs. We examined the role of 58 RTKs in sporadic/NF1-associated MPNST cell lines. Our RTK-based pharmacologic screens established that the erbB inhibitor canertinib and the IGF1 receptor (IGF1R) inhibitor picropodophyllin inhibited MPNST growth/Ras activation. Our genome-scale shRNA screens also established erbB3 and IGF1R as essential for the growth of MPNST cells. We hypothesize that MPNST growth in vivo is dependent on the action of erbB3 and IGF1R and that therapeutic regimens simultaneously targeting these key RTKs will effectively treat MPNSTs. 1) We will test the hypothesis that combinatorial therapies targeting erbB receptors and IGF1R will effectively inhibit MPNST xenograft growth in vivo. 2) We will test the in vivo role of erbB3 in tumor initiation and drug sensitivity using xenografts and a genetically engineered mouse model (GEMM). 3) We will test the hypothesis that drug relapse is mediated by “secondary” RTKs that compensate for erbB and IGF1R inhibition to drive key cytoplasmic signaling pathways. In this application, we propose an additional aim: We will test the hypothesis that NRG1β- mediated erbB3 activation promotes CCL2 secretion, which recruits M2 macrophages, and that Schwann cell secretion of CCL2 and macrophage responses to CCL2 are enhanced by decreased Nf1 gene dosage. The parental R01 focuses on the cell-autonomous role of inhibiting erbB3 and IGF1R signaling in MPNST cells, it does not address the possibility that erbB3 activation has non-cell autonomous actions that promote MPNST pathogenesis such as recruiting non-neoplastic cell types into the tumor. Establishing that erbB3 promotes MPNST pathogenesis by promoting the secretion of cytokines that recruit/activate macrophages would suggest that therapies combining erbB3 and CCL2 inhibition might be effective against MPNSTs. This work will provide Dr. Jenkins with data for her K22 application/training necessary for independence. This experimental plan will allow us to develop effective therapies for untreatable s...