The underlying premises of anti-angiogenic drug development are now being revised thanks to such discoveries as the role of VEGF and the oncogenic mutations of tumors
By supporting the growth of blood vessels that absorb nutrients and oxygen, angiogenesis allows tumors to progress from clonal populations to cell masses that can expand and ultimately metastasize. This is a well-established concept, but some of the premises underlying anti-angiogenic drug development are now being revised, according to Luisa Iruela-Arispe, PhD, of the molecular, cell and developmental biology department at the University of California, Los Angeles.
Dr. Iruela-Arispe discussed future directions in angiogenesis at a teleconference held in conjunction with AACR 2009 in Denver. The four initial premises Dr. Iruela-Arispe outlined are:
• All tumors require angiogenesis to grow and metastasize;
• The process of angiogenesis, and the features of endothelial cells, are similar among tumors. Therefore, one agent is likely to inhibit angiogenesis in all tumor types;
• Anti-angiogenic therapy will not induce drug resistance; and
• Anti-angiogenic therapy will have no effect on the quiescent vasculature.
“These four premises, or molecular underpinnings, have guided the field. But now our understanding is more sophisticated and we have learned that these ideas are not necessarily correct,” she said.
Since the initial discovery that VEGF is a critical molecule in the regulation of endothelial cell survival, an entire VEGF “family” has emerged. Its members interact with a variety of receptors that trigger events initiating angiogenesis and the survival of epithelial cells.
The most well-established anti-angiogenic agent, bevacizumab (Avastin), blocks VEGF by capturing and sequestering the ligand, which prevents it from binding to the endothelial cells, blocking signaling and thereby inhibiting the progression of angiogenesis. In the pivotal late-stage metastatic colorectal cancer trial NSABP C-08, the addition of bevacizumab to chemotherapy improved survival by about five months. The study validated the relevance of pursuing angiogenesis as a treatment for cancer (N Engl J Med 350:2335-2342, 2004).
Initial enthusiasm over the findings in the metastatic setting was tempered somewhat by the observation of bevacizumab’s toxicity profile (primarily hypertension and arteriothrombolic events) and the realization that anti-VEGF therapy does not replace chemotherapy. Also, Roche and Genentech recently announced that bevacizumab did not improve disease-free survival in a phase III adjuvant trial.