Mechanisms of tumor progression and kinome targeting in peripheral nerve sheath tumors

Tyrosine kinases (TK) are central regulators of signaling pathways that control critical activities in cells. A breakthrough in therapy for cancers associated with activating mutations in TKs is the development of imatinib mesylate for the treatment of CML and GIST tumors. Our hypothesis is that novel kinase oncogenic mutations might be implicated in the pathogenesis of tumor progression in peripheral nerve sheath tumors (PNST) and therefore potential targets to molecular inhibition. MPNSTs are highly aggressive neuroectodermal mesenchymal neoplasms, for which no effective cytotoxic or targeted chemotherapy is currently available. Our aim is to perform high throughput mutational analysis of 15 TKs in a group of 10 MPNST patients. The TKs selection will be based on their transcriptional expression level available from our previous microarray profiling. An additional 10 PNST samples will be studied on the microarray, focusing on malignant transformation in neurofibroma, to specifically address the transcriptional alterations related to tumor progression. The identified TK mutations in this pilot study will then be tested for constitutive activation and will be sought in a larger sarcoma subset.