with very minimal reversible clinical side effects.

Recent studies report that pancreatic, colon, prostate, ovarian, and head and neck neoplasms that express wild type EGFR and TGF /EGF leading to activation of EGFR in tumor associated endothelial cells respond to treatment with TKI. Moreover, retrospective analysis of a recent clinical trial of cetuximab showed that colorectal cancer patients with EGFR negative tumors could respond to E3 ligase inhibitor therapy. These have been confirmed in other clinical studies and are also consistent with recent preclinical studies using cetuximab showing that the activity of the agent was unrelated to relative total or activated EGFR expression levels. Collectively, these data recommend that predicting response of individual neoplasms to EGFR TKI can be best accomplished by careful screening of biopsy specimen for expression of the ligand TGF /EGF and phosphorylated EGFR in tumor cells and especially in tumor associated endothelial cells. The progressive growth, survival, and metastasis of neoplasms depend on the Organism development and maintenance of an adequate vascular supply. Specifically, the survival of all cells in the body depends on an adequate supply of nutrients and oxygen and removal of waste products, i. e., vascular supply. Because the genetic instability of neoplastic cells in general and metastatic cells in particular leads to the generation of biologic heterogeneity in neoplasms, targeting the neovasculature of neoplasms has been explored as an approach to therapy. Antivascular therapy can destroy tumor cells that require nutrients and oxygen for survival. Linifanib Endothelial cells in normal tissues rarely divide, whereas up to 2% to 5% of endothelial cells in neoplasms divide daily. These dividing endothelial cells should be sensitive to anticycling drugs, such as irinotecan. However, the major signaling pathways induced by activation of tyrosine kinase receptors are Akt and P13K, which can affect not only cell proliferation but also inhibition of apoptosis. In our study, inhibition of EGFR activation on tumor associated endothelial cells by PKI166 inhibited the dividing endothelial cells resistance to irinotecan and therefore induced their apoptosis leading to a marked decrease in microvessel density, decreased proliferation of tumor cells, and increased apoptosis of tumor cells. These differences between dividing tumor associated endothelial cells and quiescent endothelial cells in normal tissues allow selective therapy with EGFR TKI combined with chemotherapy. Our may provide an explanation as to why suppression of proliferation of EGFR positive tumor cells by EGFR targeting drugs?which should render the treated cancer less susceptible to chemotherapy drugs?can lead to increased chemosensitivity. If the primary targets are EGFR positive tumor associated endothelial cells, the proliferative status of the tumor cell population may be irrelevant to the effects of the chemotherapy obtained.