title: Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies.
abstract: 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.
authors.affiliation: Departments of Gynecologic Oncology and Cancer Biology, University of Texas MD Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, TX 77230-1439, USA.
authors.forename: Justin N
authors.initials: JN
authors.lastname: Bottsford-Miller
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003001:Cloning, Molecular; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism*; D057285:Precision Medicine; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D015507:Drugs, Investigational; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein