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R.E. Frink
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-098 - Acquired Resistance to Anti-VEGF Therapy in Non-Small Cell Lung Cancer Is Not Associated with Angiogenic Compensation (ID 2808)
09:30 - 09:30 | Author(s): R.E. Frink
- Abstract
Background:
The vascular system provides nutrients and oxygen to cells and tissues via the circulation of blood. Tissues require an efficient vascular network to maintain homeostasis. Angiogenesis, the process of expansion and remodeling of the vascular network, is driven by the expression and secretion of angiogenic growth factors that stimulate endothelial cell migration, proliferation and survival. Induction of angiogenesis is an early event in the progression of tumors, including non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-A (VEGF) is a principal angiogenic growth factor in NSCLC and as a result is an attractive therapeutic target. Despite promising preclinical results, therapies targeting VEGF have shown only modest improvements in progression free survival and overall survival in NSCLC patients. Many NSCLC patients that initially respond to anti-VEGF therapy develop resistance with continued use. We sought to determine factors associated with acquired resistance to anti-VEGF monoclonal antibodies (mAbs). r84 is a fully human anti-VEGF mAb that inhibits human and mouse VEGF binding to VEGF receptor 2 (VEGFR2) but not VEGFR1 and is currently in Phase I clinical trials. Bevacizumab is a humanized mAb specific for human VEGF that blocks VEGF from binding VEGFR1 and VEGFR2 and is currently approved for treatment of NSCLC.
Methods:
Acquired resistance to anti-VEGF therapy was driven in NSCLC cell lines (H1975, H1993, and H2073) by prolonged in vivo therapy with r84 or bevacizumab. Over 20 cell lines (e.g., H1975-81) were generated by ex vivo culture from tumors that displayed acquired resistance to therapy. In addition, tumor cell lines were generated from tumor-bearing mice treated with saline (e.g. H1975-713). A subset of control and resistant cell lines were implanted in vivo and evaluated for response to anti-VEGF therapy. Tumor microvessel density was determined by immunohistochemistry.
Results:
Two of five acquired resistance cell lines were verified as resistant upon reimplantation and treatment with r84 and bevacizumab demonstrating that the changes induced by prolonged anti-VEGF therapy in these cell lines are heritable. Conversely, tumor xenografts from saline control tumors remained sensitive to anti-VEGF therapy. Anti-VEGF therapy with r84 or bevacizumab reduced microvessel density in each tumor regardless of whether therapy reduced tumor growth or not.
Conclusion:
Anti-VEGF therapy significantly reduces angiogenesis even in tumors that show resistance to therapy, suggesting that compensation by other angiogenic growth factors is not a significant contributor to tumor response to anti-VEGF therapy. Further, prolonged treatment with anti-VEGF can induce heritable changes in NSCLC cells that confer resistance to anti-VEGF therapy.
