From the Steele Laboratory for Tumor Biology, Department of Radiation Oncology and the Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Supported by the National Cancer Institute and the National Foundation for Cancer Research. This article is based on an invited commissioned review for Nature Reviews Clinical Oncology.
Address reprint requests to Rakesh K. Jain, PhD, Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom St, Cox-734, Boston, MA 02114; e-mail: jain{at}steele.mgh.harvard.edu
Overview: The approval of bevacizumab, an anti-vascular endothelial growth factor (anti-VEGF) antibody, in combination with chemotherapy and the approval of oral multireceptor tyrosine kinase inhibitors that include VEGF receptors as one of their targets have changed the practice of oncology for metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic breast cancer, metastatic renal cell carcinoma, hepatocellular carcinoma, and gastrointestinal stromal tumors. They have also raised many questions: How do these therapies work in patients? Is their mechanism of action in patients the same as originally envisioned for antiangiogenic agents? Is it the same as demonstrated in animal models? Could the overall survival benefit be increased beyond few months? Why do some patients develop high-grade toxicities from antiangiogenic therapy? Why is the benefit from antiangiogenic therapies seen only in some patients? How do we preselect these patients? Why do tumors stop responding to antiangiogenic therapy? What new pathways should be targeted to prolong the duration of response and survival without increasing toxicities? How do we tailor these new therapies to individual patients? How do we schedule them with conventional therapies and various molecular therapeutics already approved or under development? The answers to these very basic questions are not known for the approved antiangiogenic agents and will be critical in choosing the appropriate agents, their dose, their schedule and in justifying their very high costs. Here we will address the above questions on the basis of preclinical and clinical data; outline challenges in identifying and validating biomarkers for response, toxicity, and resistance to antiangiogenic therapy; and discuss emerging systemic, circulating, tissue, and imaging biomarkers.
