Antiangiogenic Therapy in Cancer: A New Era Has Begun

Although the idea of utilizing antiangiogenic agents to hinder tumor growth is not new,[1] and the discovery of angiogenesis in tumors is even older,[2] this field of research is still in its infancy. Much has been learned about angiogenesis in tumor growth and development, yet the process is exceedingly complex and tightly regulated by a sophisticated interplay between pro- and antiangiogenic factors. Decades will pass before these regulatory mechanisms are well elucidated and understood. We have learned, however, from experiments with antiangiogenic agents in animal models that inhibiting angiogenesis shrinks tumors, limits further tumor growth, and prevents the formation of metastasis. Just recently, the potential of antiangiogenesis as antitumor treatment has also been demonstrated in humans and validated in large clinical trials.[3,4] The most notable example of clinical efficacy is the increase in survival found in a phase III trial when bevacizumab (Avastin), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), was added to chemotherapy in patients with metastatic colorectal cancer.[3] The success of this therapeutic modality is exciting and offers a new gleam of hope for the future of antiangiogenic agents. It now appears possible to provide targeted anticancer therapy that hinders the growth of the primary tumor, inhibits the formation of metastasis, and shows rather limited side effects compared with conventional cytotoxic chemotherapy. This success has fueled enthusiasm for future research into angiogenesis in cancer and new drugs to target it. These positive results came at an important time when other agents, such as the VEGF receptor tyrosine kinase inhibitor semaxinib (SU5416), had failed in trials[5,6] and when, in the first phase III trial, bevacizumab failed to improve survival in patients with metastatic breast cancer.[7] These failures highlight the need for additional research to illuminate the most effective targets, the optimal timing in the course of disease at which to apply these agents, and the best combinations of agents (both antiangiogenic and cytotoxic). In this supplement to ONCOLOGY, Rakesh Jain first reviews the critical role of angiogenesis in cancer and the physiologic processes and endogenous molecules that regulate angiogenesis. This review focuses specifically on the potential mechanism of action of antiangiogenic agents. Importantly, Dr. Jain reviews evidence for the concept of using antiangiogenic therapy to normalize the tumor vasculature in order to improve chemotherapy delivery, a rapidly emerging concept that tries to explain the increased efficacy observed when antiangiogenic agents are combined with conventional cytotoxic drugs. Next, Heinz-Josef Lenz reviews clinical data with agents that have been developed for their antiangiogenic properties. He discusses the only US Food and Drug Administration-approved antiangiogenic drug to date, bevacizumab, as well as numerous other agents now in clinical trials. These agents include those that target VEGF and its receptors as well as other molecular targets, including integrins, matrix metalloproteinases, and a distinct class of agents-the vascular disruptive agents-that destroy existing tumor vasculature. Finally, Clifford Hudis reviews models of tumor growth and tumor cell-kill kinetics as well as the possible clinical implications of these models for antiangiogenic therapy. Together these articles review the current state of antiangiogenic therapy with the aim of providing the most salient research in the field.

Disclosures:

Dr. Grothey receives research support from Roche. He is on the speakers' bureaus of Genentech, Roche, and Bristol-Myers Squibb.

References:

1. Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med 285:1182-1186, 1971.
2. Greene HSN: Heterologous transplantation of mammalian tumors. I. The transfer of rabbit tumors to alien species. J Exper Med 73:461-471, 1941.
3. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.
4. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004.
5. Kuenen BC, Rosen L, Smit EF, et al: Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20:1657-1667, 2002.
6. Lara PNJ, Quinn DI, Margolin K, et al: SU5416 plus interferon alpha in advanced renal cell carcinoma: A phase II California Cancer Consortium Study with biological and imaging correlates of angiogenesis inhibition. Clin Cancer Res 9:4772-4781, 2003.
7. Miller KD, Rugo HS, Cobleigh MA: Phase III trial of capecitabine (Xeloda) plus bevacizumab (Avastin) versus capecitabine alone in women with metastatic breast cancer (MBC) previously treated with anthracycline and a taxane. Breast Cancer Res Treat 76(suppl 1):S37, 2002.