Abstract 1755: Sensitization of radiotherapy and chemotherapy by adjunction of R1507 (anti-IGF-1R monoclonal antibody) in small cell lung cancer cell lines: Opportunity of translating the triple combination R1507-Cisplatin-radiotherapy
Authors: Ferte Charles , Loriot Yohann , Gombos Andrea , Calderaro Julien , Clemenson Céline , Kuenkele Klaus-Peter , Soria Jean-Charles , Deutsch Eric 
Published: August 2014

Abstract
Introduction: Insulin like growth factor receptor-1 (IGF-1R) inhibition could be a pertinent therapeutic approach in small cell lung cancer (SCLC), given the recognized activation of an IGF-1R autocrine loop.
Materials and methods: We evaluated the importance of IGF-1R axis in SCLC by assessing IGF-1R expression and Akt activation in 83 human SCLC tissue specimens. In parallel, we evaluated in vitro the efficacy of R1507, an IgG1 fully human monoclonal antibody directed to IGF-1R. R1507 effects on IGF-1R and downstream pathways were assessed using three SCLC cell lines: H69, H146 and H526. The cytotoxicity of R1507, Cisplatin and ionizing radiation (IR) was evaluated by WST-1 cell proliferation assays and clonogenic survival assays. In vivo, the efficacy of R1507, Cisplatin and IR was assessed on H526 and H146 xenografts in nude mice.
Results: IGF1R was overexpressed and Akt was activated in 38 (46%) and 31 (37%) of 83 SCLC tumors, respectively. In vitro, R1507 down-regulates IGF-1R receptor and disrupts downstream signaling through Akt and MAPK pathways in a dose dependent manner in selected small cell lung cancer cell lines. R1507 inhibits cell proliferation and colony forming capacity in H526 and H146 cells but not in H69 cells. The inhibition of PI3K-Akt pathway correlated with treatment response. The combination of R1507 (200 nM) and CDDP (3 μM) exhibited a synergistic inhibitory effect on the colony forming capacity of H146 cells and an additive inhibitory effect on H526 cells. R1507 showed synergistic effects with IR (2 Gy) in H146 cells and an additive inhibitory effect in H526 cells. R1507 potentiates the IR effects and induces a prolonged increase of the proportion of sub G1 cells in H526 but not in H146 cell line. The triple combination R1507-Cisplatin-IR potentiates the antitumoral effect of Cisplatin-IR (current standard treatment) in H146 and in H526 cell lines. In vivo, R1507 administered in monotherapy leads to a non-significant delay of tumor growth in H526 xenografts but sensitizes to both Cisplatin and IR. The triple combination R1507-Cisplatin-IR achieves a long lasting delay in tumor growth as compared with the current standard treatment Cisplatin-IR.
Conclusion: R1507 has a single agent activity and remarkable chemo- and radiosensitizing effect in defined SCLC cell lines in vitro. Efficacy is dose-dependent and related to the capacity to inhibit PI3K-Akt signaling pathway. In vivo, it sensitizes to both IR and Cisplatin effects. The triple combination R1507-Cisplatin-IR exhibits a long lasting tumor growth delay as compared with the current standard treatment Cisplatin-IR, the potential of this combination should be evaluated in further early clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1755. doi:10.1158/1538-7445.AM2011-1755