einases and disintigrin/metalloproteases and it could probably sustains a constitutive stimulation of the receptor and its downstream pathways, such as MAPK signalling. Some of these proteases are activated by other cell surface receptors called G protein coupled receptors, whose activation by specific agonists enables the EGFR transactivation Vismodegib 879085-55-9 in cancer cell. In primary breast tumors, high EGFR activity correlates with elevated levels of ADAM proteases and in prostate cancer altered expression of GPCRs and their ligands induces cancer development. It has recently been demonstrated that targeting some of these proteases, such as ADAM17, might revert the malignant phenotype in breast cancer cell lines by preventing mobilization of EGFR ligands TGF and amphiregulin.
Moreover, a strong correlation between TACE and TGF GSK1904529A 1089283-49-7 expression is observed in human breast cancers, that is predictive of poor prognosis. 3. EGFR inhibition based combinations of targeted agents 3.1. Inhibition of EGFR and VEGF pathways The tight connection between EGFR and VEGFR and the increased VEGF expression as escare pathway in the development and maintenance of anti EGFR drug resistant phenotype accounts for the rational combination of inhibitors targeting both signal transduction pathways. Several preclinical studies have provided the rational basis for such strategy, reporting an additive or even synergistic interaction. We have first demonstrated that an association of cetuximab with a human VEGF antisense 21 mer phosphorothioate oligonucleotide in human GEO colon cancer resulted in a selective inhibition of growth factor production including VEGF, bFGF and TGF and of Tortora et al.
Page 6 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript neo angiogenesis and a synergistic tumour growth inhibition in xenografted mice. Combination of the VEGFR2 antibody DC101 and cetuximab significantly inhibited the growth of TMK 1 gastric cancer, decreased tumour vascularity and increased endothelial cell apoptosis. On the basis of these encouraging data several clinical studies were initiated. Different approaches have been used to block EGFR and VEGF/VEGFR, including the combination of two specific agents and the use of multi targeted drugs.
Combination of anti EGFR mAb cetuximab with anti VEGF mAb bevacizumab provided preliminary evidence of activity and increase in time to progression in colorectal cancer patients failing several lines of chemotherapy in a study known as Bond 2. Several phase II and III studies are now ongoing in colorectal cancer patients evaluating the combination of bevacizumab with either cetuximab or the other anti EGFR mAb panitumumab. The combination of bevacizumab with the small molecule TKI erlotinib is clinically investigated in renal cell, NSCLC, colorectal and pancreatic cancer with encouraging anti tumour activity and safety data. An alternative approach is the use of multi target antagonists. AEE 788 and ZD6474/ vandetanib are two examples of orally available inhibitors of both VEGFR and EGFR dependent pathways. Phase I/II clinical studies with ZD6474 have shown good tolerability, a specific side effect being QTc prolongation, and activity in NSCLC patients previously treated with chemotherapy. We have recently demonstrated that ZD6474 may synergize with cetuximab in preclinical models. The combined blockade of EGFR and VEGF or VEGFR is thus a therap