Genomic and Molecular Characterization of Malignant Peripheral Nerve Sheath Tumor Identifies the IGF1R Pathway as a Primary Target for Treatment

Abstract

Purpose Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically altered pathways with the purpose of scanning possible therapeutic targets. Experimental design We performed a microarray based-comparative genomic hybridization (aCGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. IHC and cell biology detection and validation were performed on human MPNST tissues and cell lines. Results Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes. At the pathway level, we identified a significant enrichment of copy number–altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself. To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using immunohistochemistry. Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using small interfering RNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and MAPK pathways. Conclusion These integrated genomic and molecular studies provide evidence that the IGF1R pathway is a potential therapeutic target for patients with MPNST.

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

“…On the basis of the findings of our in vitro study, it is reasonable to say that a single use of Everolimus is a potential novel drug therapy for sporadic and NF1-related MPNSTs. However, further in vivo and in vitro investigations in combination with other kinase inhibitors or cytotoxic agents are encouraged because the mTOR inhibitor might show stronger antitumor activity when administered in combination (24,41,45,46). This study revealed that AKT/mTOR/S6RP activation was not only suitable as a treatment target, but also useful for prognostication.…”

Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling

“…46 Therefore, IGF1R has been identified as a potential molecular target for several cancer types, including breast cancer, cervical cancer, malignant melanoma and NSCLC. 47 Moreover, the activation of IGF-1R and its downstream pathways has critical roles in the normal development of many tissues and is believed to be important for the maintenance of tissue-resident adult stem cells. 48 IGF-1R-mediated signaling is also required for embryonic stem cell self-renewal, 49 indicating an important role for IGF-1R in stem cell biology.…”

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

“…As part of this effort, several laboratories have explored the possibility that aberrant growth factor signaling is a key upstream mediator of Ras activation in MPNSTs. These studies identified several growth factors and growth factor receptors that potentially contribute to neurofibroma and MPNST pathogenesis, including the epidermal growth factor (EGF) receptor, 24 neuregulin-1 (NRG1), 24 platelet-derived growth factor, 24 hepatocyte growth factor, and its c-Met receptor, 24 the insulin-like growth factor 1 receptor, 51 transforming growth factor-b1, 52 lysophosphatidic acid, 53 midkine, 52 Kit ligand and its c-Kit receptor, 24 CXCR4 and its CXCL12 ligand, 54 basic fibroblast growth factor, and vascular endothelial growth factor. 55 However, the strength of the evidence…”