Antiangiogenic Therapies for Gastrointestinal Cancers
Antiangiogenic Therapies for Gastrointestinal Cancers
Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy—namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4–Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.
As first proposed by Judah Folkman in 1971, new blood-vessel formation via angiogenesis is one of the most important steps in progression of cancer from localized to metastatic disease. The target of antiangiogenic therapy for cancer is, therefore, the tumor vasculature. Vascular endothelial growth factor (VEGF) was originally characterized as a tumor-secreted protein that increased microvascular permeability to plasma proteins: VEGF has since been recognized as one of the most important factors involved in tumor angiogenesis.
During the past decade it has been shown that increased circulating levels of VEGF correlate with advanced disease in patients with colorectal cancer or one of the four most prevalent gastrointestinal cancers—esophageal, gastric, hepatocellular and pancreatic cancer—indeed, VEGF is overexpressed by these tumors. For some types of cancer, increased VEGF expression levels in tumors are more sensitive than traditional staging methods for predicting prognosis and risk of relapse. Increased expression of VEGF in patients with colorectal cancer has been associated with tumor neovascularization, metastasis and proliferation of cancer cells.
VEGF and its receptors (VEGFRs) are overexpressed in pancreatic tumors, and this overexpression seems to be an important predictor of liver metastases and poor prognosis in patients with ductal pancreatic adenocarcinoma. VEGF can also promote the dissemination of metastases, which leads to early cancer recurrence and poor outcome. VEGF is also overexpressed in gastric and esophageal tumors, and this overexpression correlates with recurrence and worse prognosis. Hepatocellular carcinomas (HCCs) are highly vascular tumors in which VEGF is overexpressed. Tumor expression of VEGF significantly correlates with the serum VEGF level in patients with HCC, and the concentration of circulating VEGF increases with advancing HCC stage. VEGF is, therefore, a potential therapeutic target for a number of gastrointestinal cancers. In this Review, data on the activity of bevacizumab in colorectal and other gastrointestinal cancers are presented. Where applicable, current and future studies are also considered. Furthermore, some promising new targets for monoclonal antibodies and further targeted therapies that have been tested in preclinical as well as early clinical trials are discussed.
Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy—namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4–Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.
As first proposed by Judah Folkman in 1971, new blood-vessel formation via angiogenesis is one of the most important steps in progression of cancer from localized to metastatic disease. The target of antiangiogenic therapy for cancer is, therefore, the tumor vasculature. Vascular endothelial growth factor (VEGF) was originally characterized as a tumor-secreted protein that increased microvascular permeability to plasma proteins: VEGF has since been recognized as one of the most important factors involved in tumor angiogenesis.
During the past decade it has been shown that increased circulating levels of VEGF correlate with advanced disease in patients with colorectal cancer or one of the four most prevalent gastrointestinal cancers—esophageal, gastric, hepatocellular and pancreatic cancer—indeed, VEGF is overexpressed by these tumors. For some types of cancer, increased VEGF expression levels in tumors are more sensitive than traditional staging methods for predicting prognosis and risk of relapse. Increased expression of VEGF in patients with colorectal cancer has been associated with tumor neovascularization, metastasis and proliferation of cancer cells.
VEGF and its receptors (VEGFRs) are overexpressed in pancreatic tumors, and this overexpression seems to be an important predictor of liver metastases and poor prognosis in patients with ductal pancreatic adenocarcinoma. VEGF can also promote the dissemination of metastases, which leads to early cancer recurrence and poor outcome. VEGF is also overexpressed in gastric and esophageal tumors, and this overexpression correlates with recurrence and worse prognosis. Hepatocellular carcinomas (HCCs) are highly vascular tumors in which VEGF is overexpressed. Tumor expression of VEGF significantly correlates with the serum VEGF level in patients with HCC, and the concentration of circulating VEGF increases with advancing HCC stage. VEGF is, therefore, a potential therapeutic target for a number of gastrointestinal cancers. In this Review, data on the activity of bevacizumab in colorectal and other gastrointestinal cancers are presented. Where applicable, current and future studies are also considered. Furthermore, some promising new targets for monoclonal antibodies and further targeted therapies that have been tested in preclinical as well as early clinical trials are discussed.
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