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Introduction: Targeting Angiogenesis in Cancer Therapy

Department of Medical Oncology and Transplantation, Duke University Medical Center, Durham, North Carolina, USA

Correspondence: Herbert I. Hurwitz, M.D., Department of Medical Oncology and Transplantation, Box 3052, Duke University Medical Center, Durham, North Carolina 27710, USA. Telephone: 919-681-5257; Fax: 919-684-9712; e-mail: hurwi004{at}mc.duke.edu

Since the hypothesis of targeting angiogenesis to treat cancer was first described in 1971 by Judah Folkman, there has been intense research into the development of antiangiogenic cancer therapies. A number of angiogenesis inhibitors are currently in clinical development. These agents include small molecules, peptides, antibodies, and complex proteins. The number of potential antiangiogenesis targets for cancer is large, and growing.

Vascular endothelial growth factor (VEGF) is a proangiogenic factor known to play a central role in tumor angiogenesis and has, therefore, emerged as a promising target for therapeutic intervention. Several potential anti-VEGF strategies are currently under investigation. The best studied of these approaches include inhibition of VEGF and VEGF receptor activity with monoclonal antibodies and inhibition of receptor signaling with tyrosine kinase inhibitors.

Bevacizumab (rhuMAb VEGF; Avastin^TM; Genentech, Inc.; South San Francisco, CA), a recombinant humanized monoclonal antibody directed to VEGF, is at an advanced stage in clinical development. By inhibiting the activity of VEGF, bevacizumab prevents intracellular signal transduction and the consequent migration and proliferation of endothelial cells that initiate new blood vessel formation. Preclinical studies have demonstrated that these effects of bevacizumab can cause inhibition of tumor neovascularization, thereby preventing tumor growth.

At The Second Annual Solid Tumor Investigators’ Meeting, Scottsdale, AZ, September 26-29, 2002, presentations outlined the development of antiangiogenic therapies, such as bevacizumab, in cancer therapy. The articles presented in this supplement highlight key findings from that meeting and provide an overview of the history, current status, and future prospects of bevacizumab in clinical practice.

In the opening article, Napoleone Ferrara provides an overview of tumor angiogenesis and illustrates the importance of VEGF in this process and the rationale for targeting tumor-expressed VEGF as a cancer therapy. Targeting VEGF in the treatment of non-small cell lung cancer is described by Roy Herbst and Alan Sandler. Trials have shown superior response rates with the addition of bevacizumab to chemotherapy regimens, particularly in patients with nonsquamous histologies. There also has been much interest in the potential of anti-VEGF therapies in breast cancer, particularly with regard to tailoring treatment according to the VEGF expression profile of certain forms. Hope Rugo reviews progress in this area and discusses bevacizumab alone and in combination with chemotherapy. Data from a phase III trial of bevacizumab in combination with capecitabine in second-line metastatic breast cancer are discussed. Nishan Fernando and I describe the rationale for targeting VEGF in colorectal cancer and discuss the completed and ongoing phase II and phase III studies. Helen Chen continues the theme with a review article exploring the clinical development of bevacizumab in various tumor types, both as monotherapy and as part of combination regimens with chemotherapy or other biologically targeted therapies. Finally, Emily Bergsland and Maura Dickler review challenges to be overcome in the continued clinical development of bevacizumab and the integration of bevacizumab into current treatment regimens to ensure that optimal use in cancer patients is achieved.

Although the concept of angiogenesis inhibition as a treatment strategy for cancer was proposed over three decades ago, its impact on clinical practice has, at times, seemed uncertain. However, recent positive phase III data with bevacizumab in colorectal cancer suggest that the time has finally come to include bevacizumab among the therapeutic options for the treatment of cancer.

Received November 25, 2003; accepted for publication January 15, 2004.

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