Mechanisms And Combinational Therapy Enhances Effects Of Anti-IGF-1R MAb To Target Lung Cancer

Part one:Association between Circulating Levels of IGF-1 and IGFBP-3 and Lung Cancer Risk:A Meta-AnalysisPurpose:The insulin-like growth factor (IGF) system was documented to play a predominant role in neoplasia. As lung cancer is one of the most malignant cancers, we conducted a meta-analysis in order to investigate the strength of association between circulating IGF-1 and IGFBP-3 levels and lung cancer.Methods:A systematic literature search was conducted to identify all prospective case-control studies and case-control studies on circulating IGFs and IGFBPs levels. Six nested case-control studies (1043 case subjects and 11472 control participants) and eight case-control studies (401 case subjects and 343 control participants) were included in this meta-analysis. Pooled measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted OR with 95%CIs for highest vs. lowest levels to assess the association of circulating IGF-1 and IGFBP-3 concentrations and lung cancer. Standard mean difference (SMD) was also calculated to indicate the difference of the circulating IGF-1 and IGFBP-3 concentrations between the lung cancer case group and the control group.Results:Of the nested case-control studies, ORs for the highest vs. lowest levels of IGF-1 and IGFBP-3 were 1.047 (95% CI:[0.802,1.367], P=0.736) and 0.960 (95%CI:[0.591,1.559], P=0.868) respectively; and SMDs were-0.079 (95%CI:[-0.169,0.011], P=0.086) and-0.097 (95%CI:[-0.264,0.071], P=0.258) for IGF-1 and IGFBP-3 respectively. As to the case-control studies, SMDs were 0.568 (95%CI:[-0.035,1.171], P=0.065) and-0.780 (95%CI:[-1.358,-0.201], P=0.008) for IGF-1 and IGFBP-3 respectively.Conclusion:Inverse association was shown between IGFBP-3 and lung cancer in the case-control studies, and the circulating level of IGFBP-3 underwent a decline during tumorogenesis and development of lung cancer, which suggested IGFBP-3 a promising candidate for the biomarker of lung cancer.Part two:Mechanisms and Combinational Therapy Enhances Effects of Anti-IGF-1R mAb to Target Small Cell Lung CancerPurpose:Small cell lung cancer (SCLC) is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality.Methods:We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP) on SCLC, and tried two drug combinations to improve CP therapy.Results:Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. How-ever, we observed elevatedMEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by β-arrestinl knockdown while attenuated by β-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation.Conclusion:Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strat-egy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies.Part three:Mechanisms and Combinational Therapy Enhances Effects of Anti-IGF-1R mAb to Target Non-Small Cell Lung CancerPurpose:The insulin-like growth factor (IGF) signaling system plays a critical role in tumorigenesis, highlighting the potential of targeting IGF-1R as an anti-cancer therapy. Although multiple anti-IGF-1R monoclonal antibody (mAb) drugs have been developed, challenges remain in the validation of the therapeutic effects and understanding the molecular mechanism of these mAbs. We tested the anti-tumor effects of an anti-IGF-1R mAb Figitumumab to a series of non-small cell lung cancer (NSCLC) cell lines, and try to illustrate the possible mechanisms. Further, we tried the combination of MER/ERK inhibitor and metformin to Figitumumab seeking for therapeutic enhance effects.Methods:MTT was used to test the cell viability of NSCLC cell lines after treatments. And Western blot was used to detect the activation of IGF-1R signaling pathway and the IGF-IR down-regulation status.Results:we conducted a study to validate the effect of Figitumumab (CP), an anti-IGF-1R mAb, in a panel of cell lines. We found all tested NSCLC cell lines were sensitive to Figitumumab, and Figitumumab could block IGF-1R and the downstream PI3K/AKT pathway activation. Unexpectedly, we found Figitumumab could activate ERK signaling pathway in IGF-1R kinase independent manner, which we further verified was mainly mediated by (3-arrestin2. We also investigated the anti-tumor effect of metformin alone as well as its combination with Figitumumab to target NSCLC. Metformin could target IGF-1R signaling pathway by attenuating PI3K/AKT and MEK/ERK signaling pathways and down-regulating IGF-1R. Finally, we found that combining metformin with CP Figitumumab could further induce IGF-IR down-regulation and was more effective to target NSCLC cells.Conclutions:Our study confirmed the anti-tumor effect of Figitumumab to NSCLC, and we illustrated the signaling blocking and receptor down-regulation effects of Figitumumab to NSCLC. Moreover, our data supportes the combining of metformin with CP has additive therapeutic value against NSCLCPart four:The Synergistic Effect of Humanized Monoclonal Antibodies Targeting Insulin-Like Growth Factor 1 Receptor (IGF-1R) and Chemotherapy Purpose:IGF-1R, an important member of the IGF signaling system, is a plasma-membrane-bound receptor composed of twoa-subunits and two β-subunits. IGF-1R has been revealed to play a pivotal role in cancer cell proliferation, differentiation, apoptosis and phenotype transformation, resulting uncontrolled tumor-cell growth. During the last decades, IGF-1R monoclonal antibody combined with chemotherapeutic agents as a novel cancer treatment approach has shown synergistic effect in cancer treatment in some preclinical and clinical trials.This work attempts to provide convincible evidence to warrant further investigation to identify prognostic biomarkers on neoplasm by reviewing all the relative clinical trials.Methods:We summarized the role of IGF-1R system in carcinogenesis, and the preclinical and clinical studies about anti-IGF-1R targeting therapy. And we system searched the clinical trials about the combinational therapy, and extracted the details mentioned in those studies.Results:Herein, we summarized the recent online and published literatures concerning the safety, tolerability, anti-tumor activity and adverse events of this novel strategy. Prolonged progression-free survival rate, objective response rate and stable disease were shown in some sorts of cancer patients compared to those implemented traditional standard chemotherapy. However, not all related clinical trials demonstrated expected promising outcomes. Most treatment-related adverse events in those studies are mild and manageable. The most frequently happened side effect is hyperglycemia in majorities of combined cancer therapy studies.Conclusion:The involvement of the IGF-1 and IGF-1R axis in tumor genesis makes it an attractive target for anti-cancer treatment. The IGF signaling system also plays an essential role in the resistance to a variety of clinically useful cancer therapies. Some phase I/II trials are supportive of the synergistic effect by combining mAbs and chemotherapy agents, while some are not satisfactory as expected. Based on the favorable preclinical studies of mAbs, we are still in confidence with this strategy. There is an urgent requirement of seeking novel biomarkers for resistance and sensitivity, de veloping rational therapeutic regimen, and elucidating the mechanisms of drug resistance on the basis of Evidencebased Medicine.