Combination of Metformin and Statins Significantly Enhanced the Local Radio therapeutic Effect and Attenuated the Lung Metastasis of Lewis Lung Carcinoma (LLC) Animal Model

Purpose/Objective(s): Interaction between the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGF-1R) has been well established inmany cancer types. Ligands of these receptors are capable of activating both pathways. We investigated the effects of cetuximab (EGFR antibody) and IMC-A12 (IGF-1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (IR). Materials/Methods: SixHNSCCmodels expressing different levels of EGFR and IGF-1R were studied. The effects of cetuximab and IMC-A12 on cell viability (MTS assay) and radiosensitivity (clonogenic survival assay) were determined. Formation of nuclear g-H2AX and 53BP1 foci was monitored by immunofluorescence to assess the IR-induced DNA damage and repair kinetics. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of IMCA12 in enhancing tumor response to cetuximab and radiation using two HNSCC tumor xenograft models generated in mice. Results: In vitro studies in six HNSCC lines showed that exposure to cetuximab resulted in increased cell radiosensitivity in two cell lines. EGFR inhibition suppressed DNA repair that was evident by the prolonged presence of nuclear g-H2AX and 53BP1 foci. Western blot analyses showed that EGFR inhibition increased IGF-1R expression levels and also the association between EGFR and IGF-1R. When IMC-A12 was added concurrently to the treatment regimen along with cetuximab, a further increase in radiosensitivity was observed in one of the three cell lines tested. In vivo tumor growth delay data in two of the HNSCC tumor models showed that tumor xenografts exhibited enhanced tumor response to RT in the presence of either cetuximab or IMC-A12 depending on the tumor type. Addition of IMC-A12 to cetuximab and IR treatment regimen failed to further enhance the tumor response to cetuximab as well as to IR. Conclusions: Taken together our data suggest that concomitant inhibition of both EGFR and IGF-1R pathways using their respective antibodies did not yield additional therapeutic benefit in overcoming resistance to RT. Author Disclosure: U. Raju: None. D.P. Molkentine: None. D.R. Valdecanas: None. A.A. Deorukhkar: None. K.A. Mason: None. T.A. Buchholz: None. R.E. Meyn: None. K.K. Ang: None. H. Skinner: None.