When evaluated in combination with gemcitabine and capecitabine in a phase II trial bevacizumab did not improve survival. Despite the intial excitement, bevacizumab failed Checkpoint kinase inhibitor to improve survival in advanced pancreas cancer patients when evaluated in combination with standard of care. Several tiny molecular tyrosine kinase inhibitors against VEGFR2, including sorafenib, sunitinib and vatalatinib, have being examined in the illness but none showed positive efficacy sign to date. Combination therapies targeting VEGFRs and other signaling pathways are under study. Insulin like growth factor pathway The IGF axis consists multiple moving ligands, such as IGF 1, insulin and IGF II, getting together with membrane bound receptors, such as form I IGF receptor. The PI3k Akt pathway is one primary downstream mediator of IGF 1R signaling and represents a potentially important role in anticancer drug resistance. IGF 1R has been shown in preclinical studies to mediate resistance to EGFR inhibition, and co targeting of both receptors increases the abrogation of PI3k Akt activity and reduces survivin term. Transgeneic mouse models of pancreas cancer Digestion showing high quantities of IGF 1R showed improved invasive carcinomas and lymph node metastases. Targeting of IGF 1R expression by siRNAs achieved growth inhibition in many gastrointestinal malignancies, suggesting potential significance of the pathway in pancreas cancer. In show, adjusting IGF 1R copy number by cDNA plasmid increased mitogenic response in mouse embryo. Treatments with MoAb appeared to bring about IGF 1R internalization and degradation, and improved cytotoxic chemotherapy effects. DNA fix pathways are other downstream effectors of IGF 1R axis and provide the explanation for combining IGF 1R inhibitors with cytotoxics. A variety of agents targeting IGF 1R, both MoAbs and TKIs, are been evaluated clinically and we are beginning to recognize their clinical role and potential mechanisms of resistance to this class of drugs. Anti IGF 1R monoclonal antibodies AMG 479 is really a fully humanized MoAb that blocks the binding of IGF I and IGF II to IGF 1R, and does not cross react with all the insulin receptor. AMG 479 totally restricted l igandinduced dimerization and activation of IGF 1R/IGF 1R and IGF 1R/IR in two pancreas cancer cell lines. The antibody paid down IGF 1R mediated downstream Akt phosphorylation with professional apoptotic and anti-proliferative effects in the cancer cell lines. The adviser demonstrated additive effects with gemcitabine in pre-clinical studies. In a randomized phase II trial, AMG 479 in combination with gemcitabine demonstrated a trend to improvement in median survival when comparing to the placebo/gemcitabine control-arm in previously untreated metastatic pancreas cancer patients. The median PFS was 5. 1 weeks and 2. 1 months respectively. The researchers conclude that there was sufficient efficacy signal to warrant further analysis in a phase III trial.