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Trans-NIH Angiogenesis Workshop; May 20-21, 2013
  • Abstracts

    Normalizing Vasculature using Anti-angiogenic Agents for Treatment of Cancer and Other Diseases: Bench to Bedside to Biomarkers

    Rakesh K. Jain, PhD  [ View bio ]
    (E.L. Steele Laboratory of Tumor Biology, Harvard Medical School and Massachusetts General Hospital)

    For almost four decades, our research has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment—characterized by hypoxia, low pH, high interstitial fluid pressure, and solid stress—fuels tumor progression and treatment resistance, we developed an array of novel imaging technologies and animal models as well as mathematical models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and the extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce "normalization" of the microenvironment can improve the treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents—originally designed to starve tumors—could transiently "normalize" tumor vasculature, alleviate hypoxia, increase delivery of drugs and anti-tumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in newly diagnosed and recurrent glioblastoma patients supported this concept, revealing that the patients whose tumor blood perfusion increased in response to cediranib survived 6-9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also explained how anti-VEGF agents could improve vision in patients with wet age-related macular degeneration and opened doors to treating other nonmalignant diseases harboring abnormal vasculature, such as neurofibromatosis-2, which can lead to deafness. More recently, we discovered that blocking PlGFx—a member of the VEGF family—could block the growth and spread of pediatric medulloblastoma.

    References

    1. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nature Medicine, 7: 987-989 (2001).
    2. Winkler F et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, Angiopoietin-1, and matrix metallproteinases. Cancer Cell 6: 553-562, (2004).
    3. Jain RK. Normalization of the tumor vasculature: An emerging concept in anti-angiogenic therapy of cancer. Science 307: 58-62 (2005).
    4. Plotkin SR et al. Hearing improvement after bevacizumab in patients with neurofibromatosis 2. New England Journal of Medicine 361: 358-369 (2009).
    5. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298-307 (2011).
    6. Goel S et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiological Reviews 91: 1071–1121 (2011).
    7. Chauhan VP et al. Normalization of tumor blood vessels improves the delivery of nanomedicines in a size dependent manner. Nature Nanotechnology 7: 383-8 (2012).
    8. Stylianopoulos T et al. Causes, consequences and remedies for growth-induced solid stress in murine and human tumors. PNAS 109:15101-8 (2012).
    9. Snuderl M et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152: 1065–1076 (2013).
    10. Huang Y et al. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Research (2013).
    11. Emblem KE et al. Vascular architecture imaging identifies patient responders to anti-angiogenic therapy. Nature Medicine (2013).
    12. Jain RK. Normalizing tumor microenvironment to treat cancer: Bench to bedside to biomarkers. J Clinical Oncology (2013).


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Workshop Organizer: NIH

NCI:Nancy Emenaker, PhD, RD
Suzanne Forry-Schaudies, PhD
NHLBI:Yunling Gao, MD, PhD
NIDDK: Teresa Jones, MD

NIH - National Institutes of Health: Turning Discovery Into Health


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