Evaluation of combined insulin-like growth factor type 1 (IGF1R) and mTOR pathway blockade in sarcoma xenograft models Free

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The insulin-like growth factor and mTOR pathways have been connected to sarcoma development and progression. Preliminary data suggests that mTOR pathway inhibition can slow growth of sarcoma xenografts, including rhabdomyosarcoma. Unfortunately mTOR inhibition alone does not eliminate tumors and appears to secondarily upregulate phosphorylation of phospho-AKT in sarcomas. We therefore hypothesized that using a combination of IGF1R and mTOR pathway blockade using h7C10 (IGF1R antibody) and rapamycin respectively will lead to improved antitumor activity and prevent deleterious upregulation of phospho-AKT. Using rhabdomyosarcoma (RMS) cell lines and xenografts, we found that the IGF-1 receptor antibody (h7C10) alone decreased alveolar RMS (Rh30) cell number by 50% at 48hrs, but had inconsistent effect on an embryonal RMS (RD) cell line as measured by MTT assay (10ug/mL at 48hrs). h7C10 decreased phospho-AKT in Rh30 cell lysates (10ug/mL at 48hrs). Surprisingly, in vivo growth (measured by mean chemiluminescent intensity units) of established Rh30 cells expressing luciferase (Rh30-Luc) in SCID/beige mice was significantly decreased with h7C10 monotherapy (52.2±25.3) compared to mice treated with vehicle control (19mm±0.82) by day 36. The combination of h7C10 and rapamycin yielded results similar to h7C10 (11.9±10.4, p<0.001), whereas single agent rapamycin had no significant effects (55±20.6, p=0.7) at this time point. Continued longitudinal assessments are underway. Preliminary results suggest promising activity of IGF1R pathway blockade using the h7C10 antibody in sarcoma primary tumor as a single agent and in combination with mTOR inhibition.