Chelsea Crovetti

Introduction. Anaplastic astrocytomas (AAs) are grade 3 gliomas distinguished from low grade gliomas by higher malignancy, increased proliferation rate, and genetic mutation markers^1-9. Patients, usually 30-50 years of age, undergo complete resection of this tumor, and then follow a stringent course of radiation and chemotherapy^1-3,5,7. Problematically, these resected AAs reoccur as more aggressive, variably chemo-resistant, angiogenic secondary glioblastoma multiformes (sGBMs) with a much poorer prognosis^1,4-9. Previous studies have identified the PTPRZ1-MET fusion gene as a common mutation between AAs and sGBMs and how it produces an “always-on” phosphorylated MET, inducing cell proliferation, migration, and angiogenesis¹. This study identifies a co-occurring MET mutation in this specific cohort of patients and demonstrates even further how application of a novel MET inhibitor, PLB-1001, blocks these over proliferative effects⁵. Methods. To elucidate the sGBM mutational landscape, 188 sGBM genomic data were analyzed. After identification of a METex14 skipping mutation, the effect of increased MET signaling on STAT3, a downstream molecule in the MET pathway, was examined with immunohistochemistry and histology staining. Lentiviral vectors encoding ZM fusion and METex14 were transduced into a U87MG glioblastoma (GBM) mouse line. Subcutaneous xenografts treated with the MET-inhibitor PLB-1001 were then implanted intracranially⁵. Results. In analysis of the sGBM mutational landscape, both ZM fusion and METex14 skipping were identified to co-occur and found to be highly conserved in these high grade gliomas compared to primary GBM and low grade gliomas. The mutation, METex14 skipping, inhibited phosphorylation of the juxtamembrane component of the kinase, preventing its ubiquination and degradation. This subsequently prolonged MET’s stabilization and hyper-activated MET signaling and its downstream pathways such as STAT3, PI3K, and RAS. The novel potent MET-inhibitor, PLB-1001, demonstrated greater affinity for the ATP binding site on MET than crizotinib, a heavily studied MET inhibitor proven to reduce MET’s overactive effects, and inhibited the phosphorylation of STAT3, marking its inhibition of downstream MET signaling. In ZM-harboring U87 MG xenograft models, PLB-1001 was shown to reduce tumor volume by inhibition of MET signaling, proliferation, and uniquely angiogenesis⁵. Conclusions. Identification of ZM fusion and METex14 skipping as co-occurring mutations unique to AAs and sGBMs presents a highly specific MET signaling mechanism as a novel therapeutic target that can be specifically targeted by MET inhibitors such as PLB-1001. Although small, the subset of patients who present with these specific mutated tumors now have hope for possible future individualized therapies that show promise for better prognosis.

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