Abstract
10025 Background: aRMS is a pediatric solid tumor with a poor prognosis despite aggressive therapy. HGF/c-Met & PTEN-PI3K-AKT pathways are aberrant, leading to aRMS growth & metastasis. We hypothesize that recapitulating the tumor suppressor (TS) function of PTEN with small molecular inhibitors (SMIs) may control aRMS. SMIs of HGF/c-Met & PI3K pathways were examined for their control of aRMS growth & migration. Design/Methods: Pax3/fkhr-associated aRMS cells, RH30, were infected with MIEG3/PTEN (RH30MP1), MIEG3 retroviral vector (RH30MV1) or CMV-driven luciferase (RH30Luc). Migration was assessed by a transwell migration chamber; proliferation with a MTT assay; biochemical analysis by Western blot. Tumor growth and spontaneous lung metastasis in IACUC-approved animal experiments, in which cell lines were injected s.c. in nude mice, were analysed by bioluminescent imaging (BLI) or by direct measurements. Students t-test (p<.05) determined significance. Results: Western analysis revealed RH30 cells have low PTEN, high levels of c-Met & p-AKT. HGF stimulation of RH30 cells results in increased p-Met, p-Akt & p-Erk1/2 levels, correlating with enhanced migration and proliferation (<.001). SMI of PI3K (LY294002) controls RH30 proliferation (p<.01), not migration; c-Met (PHA665752) & MAPK (PD98059) SMIs stop HGF-directed migration through control of p-Erk levels (p<.01). PTEN induction in RH30 cells via PPAR-gamma agonist, rosiglitazone, results in decreased basal p-Akt levels. RH30 cells with stable, retroviral-infected PTEN have significantly reduced migration& proliferation as compared to cells with vector alone (p<.001). In nude mice xenograft models, PTEN & novel PI3K SMI, SF1126 at 50mg/kg, control RH30 tumoriginesis. SF1126 also controls spontaneous RH30Luc metastasis to the lungs. Conclusions: High c-Met-expressing RH30 cells are sensitive to HGF-stimulated migration through MAPK & proliferation via PI3K. PTEN’s control of aRMS migration, proliferation & tumorigenesis suggests that PTEN controls both PI3K & MAPK. Novel PI3K inhibitor, SF1126, controls tumor growth in vivo & prevents spontaneous lung metastasis. Recapitulating PTEN TS function with SF1126 alone or in combination with SMIs of the HGF/c-Met or MAPK may benefit patients with aRMS & deserves further pre-clinical study. [Table: see text]
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