期刊
JOURNAL OF CLINICAL ONCOLOGY
卷 30, 期 32, 页码 4026-4034出版社
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2012.41.9242
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资金
- Gynecologic Cancer Foundation
- National Institutes of Health (NIH) [CA 110793, 109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599, U54 CA151668]
- Ovarian Cancer Research Fund (Program Project Development grant)
- Department of Defense [OC073399, W81XWH-10-1-0158, BC085265]
- Zarrow Foundation
- Marcus Foundation
- Estate of C.G. Johnson Jr
- Gilder Foundation
- Betty Anne Asche Murray Distinguished Professorship
- Ann Rife Cox Chair in Gynecology and Cancer Prevention Research Institute of Texas [RP120214, RP110595]
- National Cancer Institute, Department of Health and Human Services, NIH [CA101642]
- Ovarian Cancer National Alliance
- sanofi-aventis
- Amgen
- Novartis
- Merck
- Merrimack Pharmaceuticals
Angiogenesis has long been considered an important target for cancer therapy. Initial efforts have primarily focused on targeting of endothelial and tumor-derived vascular endothelial growth factor signaling. As evidence emerges that angiogenesis has significant mechanistic complexity, therapeutic resistance and escape have become practical limitations to drug development. Here, we review the mechanisms by which dynamic changes occur in the tumor microenvironment in response to antiangiogenic therapy, leading to drug resistance. These mechanisms include direct selection of clonal cell populations with the capacity to rapidly upregulate alternative proangiogenic pathways, increased invasive capacity, and intrinsic resistance to hypoxia. The implications of normalization of vasculature with subsequently improved vascular function as a result of antiangiogenic therapy are explored, as are the implications of the ability to incorporate and co-opt otherwise normal vasculature. Finally, we consider the extent to which a better understanding of the biology of hypoxia and reoxygenation, as well as the depth and breadth of systems invested in angiogenesis, may offer putative biomarkers and novel therapeutic targets. Insights gained through this work may offer solutions for personalizing antiangiogenesis approaches and improving the outcome of patients with cancer. J Clin Oncol 30:4026-4034. (C) 2012 by American Society of Clinical Oncology
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