Targeting PDGFRa-activated Glioblastoma through Specific Inhibition of SHP-2-mediated Signaling
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ABSTRACT: SHP-2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is critical for PDGFR-driven gliomagenesis. SHP099, a novel and potent SHP-2 inhibitor, preferentially attenuated the tumorigenicity of GBM and glioma stem-like cells (GSCs) compared to normal brain cells or neural progenitor cells in vitro. Delivered orally, SHP099 crosses the blood-brain barrier (BBB) and accumulates at efficacious concentrations in the brains, as determined using two different orthotopic xenograft models. SHP099 inhibited tumor growth and extended survival in activated PDGFR-signaling xenografts alone and in combination with first-line chemotherapeutic agent, temozolomide (TMZ). This study highlights SHP-2 inhibitor SHP099 potential for treatment of clinical GBM in combination with TMZ.
ORGANISM(S): Mus musculus
PROVIDER: GSE126892 | GEO | 2021/02/20
REPOSITORIES: GEO
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