Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer

Nature Reviews Cancer volume 8, pages 309–316 (2008)Cite this article

Abstract

The importance of multidisciplinary translational clinical trials is obvious; however, making them work is complex and challenging. Here I present an argument for designing and implementing multidisciplinary mechanistic trials and present the lessons our team at the Massachusetts General Hospital Cancer Center has learned from two such trials in cancer patients with locally advanced rectal carcinomas and recurrent glioblastomas.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schema of the rectal carcinoma trial and the glioblastoma trial.
Figure 2: Timeline to complete various steps in each trial.
Figure 3: Normalization hypothesis.
Figure 4: Response of recurrent glioblastoma multiforme to cediranib as measured by a suite of magnetic resonance imaging (MRI) protocols.

References

  1. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145–147 (2004).

    Article  CAS  Google Scholar 

  2. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    Article  CAS  Google Scholar 

  3. Jain, R. K. Taming vessels to treat cancer. Sci. Am. 298, 56–63 (2008).

    Article  Google Scholar 

  4. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  Google Scholar 

  5. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nature Med. 7, 987–989 (2001).

    Article  CAS  Google Scholar 

  6. Yuan, F. et al. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc. Natl Acad. Sci. USA 93, 14765–14770 (1996).

    Article  CAS  Google Scholar 

  7. Jain, R. K. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 95, 10820–10825 (1998).

    Article  CAS  Google Scholar 

  8. Hansen-Algenstaedt, N. et al. Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy. Cancer Res. 60, 4556–4560 (2000).

    CAS  PubMed  Google Scholar 

  9. Lee, C. G. et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60, 5565–5570 (2000).

    CAS  PubMed  Google Scholar 

  10. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).

    Article  CAS  Google Scholar 

  11. Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004).

    Article  CAS  Google Scholar 

  12. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1 and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

    CAS  PubMed  Google Scholar 

  13. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  Google Scholar 

  14. Chen, W. et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F]fluorothymidine positron emission tomography: a pilot study. J. Clin. Oncol. 25, 4714–4721 (2007).

    Article  CAS  Google Scholar 

  15. Fine, H. A. et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J. Clin. Oncol. 18, 708–715 (2000).

    Article  CAS  Google Scholar 

  16. Herbst, R. S. et al. Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin. J. Clin. Oncol. 20, 3804–3814 (2002).

    Article  CAS  Google Scholar 

  17. Ince, W. L. et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J. Natl Cancer Inst. 97, 981–989 (2005).

    Article  CAS  Google Scholar 

  18. Jubb, A. M. et al. Impact of vascular endothelial growth factor-A expression, thrombospondin 2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J. Clin. Oncol. 24, 217–227 (2006).

    Article  CAS  Google Scholar 

  19. Lee, L. et al. Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer Chemother. Pharmacol. 57, 761–771 (2006).

    Article  CAS  Google Scholar 

  20. Liu, G. et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: Results from a phase I study. J. Clin. Oncol. 23, 5464–5473 (2005).

    Article  CAS  Google Scholar 

  21. Mancuso, P. et al. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108, 452–459 (2006).

    Article  CAS  Google Scholar 

  22. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21, 3955–3964 (2003).

    Article  CAS  Google Scholar 

  23. Motzer, R. J. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 16–24 (2006).

    Article  CAS  Google Scholar 

  24. Mross, K. et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur. J. Cancer 41, 1291–1299 (2005).

    Article  CAS  Google Scholar 

  25. Norden-Zfoni, A. et al. Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin. Cancer Res. 13, 2643–2650 (2007).

    Article  CAS  Google Scholar 

  26. Provenzale, J. M. et al. Correlation of relative permeability and relative cerebral blood volume in high-grade cerebral neoplasms. Am. J. Roentgenol. 187, 1036–1042 (2006).

    Article  Google Scholar 

  27. Vredenburgh, J. J. et al. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas. J. Clin. Oncol. 24 (June 20 Suppl.) 1506 (2006).

    Google Scholar 

  28. Wedam, S. B. et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 24, 769–777 (2006).

    Article  CAS  Google Scholar 

  29. Xiong, H. Q. et al. A phase I surrogate endpoint study of SU6668 in patients with solid tumors. Invest. New Drugs 22, 459–466 (2004).

    Article  CAS  Google Scholar 

  30. Boucher, Y., Kirkwood, J. M., Opacic, D., Desantis, M. & Jain, R. K. Interstitial hypertension in superficial metastatic melanomas in humans. Cancer Res. 51, 6691–6694 (1991).

    CAS  PubMed  Google Scholar 

  31. Boucher, Y., Salehi, H., Witwer, B., Harsh, G. R. 4th & Jain, R. K. Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br. J. Cancer 75, 829–836 (1997).

    Article  CAS  Google Scholar 

  32. Less, J. R. et al. Interstitial hypertension in human breast and colorectal tumors. Cancer Res. 52, 6371–6374 (1992).

    CAS  PubMed  Google Scholar 

  33. Roh, H. D. et al. Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response. Cancer Res. 51, 6695–6698 (1991).

    CAS  PubMed  Google Scholar 

  34. Padera, T. et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883–1886 (2002).

    Article  CAS  Google Scholar 

  35. Willett, C. G. et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J. Clin. Oncol. 23, 8136–8139 (2005).

    Article  Google Scholar 

  36. Duda, D. G., Cohen, K. S., Scadden, D. T. & Jain, R. K. A protocol for phenotypic detection and enumeration of circulating endothelial cells and circulating progenitor cells in human blood. Nature Protoc. 2, 805–810 (2007).

    Article  CAS  Google Scholar 

  37. Segers, J. et al. Potentiation of cyclophosphamide chemotherapy using the antiangiogenic drug thalidomide: Importance of optimal scheduling to exploit the normalization window of the tumor vasculature Cancer Lett. 244, 129–135 (2006).

    Article  CAS  Google Scholar 

  38. Batchelor, T. T. et al. A multidisciplinary phase II study of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Proc. Am. Assoc. Cancer Res. Ann. Meeting Abstract 5531 (2008).

  39. Horowitz, N. S. et al. A multidisciplinary phase II study of bevacizumab combined with oxaliplatin, gemcitabine in women with recurrent mullerian carcinoma. Proc. Am. Assoc. Cancer Res. Ann. Meeting Abstract 4484 (2008).

  40. Willett, C. G. et al. Evaluation of the effects of anti-VEGF therapy in a multidisciplinary phase I/II study of neoadjuvant bevacizumab with chemoradiation therapy in rectal cancer. Proc. Am. Assoc. Cancer Res. Ann. Meeting Abstract 4457 (2008).

  41. Zhu, A. X. et al. Efficacy, safety, and changes in blood markers following sunitinib monotherapy in patients with advanced hepatocellular carcinoma: Experience from a multidisciplinary phase II study. Proc. Am. Assoc. Cancer Res. Ann. Meeting Abstract 4464 (2008).

  42. Giantonio, B. J. et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J. Clin. Oncol. 25, 1539–1544 (2007).

    Article  CAS  Google Scholar 

  43. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    Article  CAS  Google Scholar 

  44. Sandler, A. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).

    Article  CAS  Google Scholar 

  45. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    Article  CAS  Google Scholar 

  46. Motzer, R. J. et al. Sunitinib versus interferon α in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    Article  CAS  Google Scholar 

  47. Willett, C. G. et al. Complete pathological response in T4 locally advanced rectal cancer after treatment with bevacizumab and standard chemo-radiotherapy. Nature Clin. Pract Oncol. 4, 316–321 (2007).

    Article  CAS  Google Scholar 

  48. Horsman, M. R. & Siemann, D. W. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies. Cancer Res., 66, 11520-11539 (2006).

  49. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    Article  CAS  Google Scholar 

  50. Ellis, L. M. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin. Oncol. 33, S1–7 (2006).

    Article  CAS  Google Scholar 

  51. Jain, R. K., Duda, D. G., Clark, J. W. & Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clin. Pract Oncol. 3, 24–40 (2006).

    Article  CAS  Google Scholar 

  52. Kerbel, R. S. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312, 1171–1175 (2006).

    Article  CAS  Google Scholar 

  53. Verheul, H. M. W. & Pinedo, H. M. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nature Rev. Cancer 7, 475–485 (2007).

    Article  CAS  Google Scholar 

  54. Dvorak, H. F. Discovery of vascular permeability factor (VPF). Exp. Cell Res. 312, 522–526 (2006).

    Article  CAS  Google Scholar 

  55. Jain, R. K. et al. Angiogenesis in brain tumours. Nature Rev. Neurosci. 8, 610–622 (2007).

    Article  CAS  Google Scholar 

  56. Sorensen, A. G., Batchelor, T. T., Wen, P. Y., Zhang, W. T. & Jain, R. K. Response criteria in glioma. Nature Clin. Pract Oncol. (in the press).

  57. Ferrara, N., Damico, L., Shams, N., Lowman, H. & Kim, R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26, 859–870 (2006).

    Article  Google Scholar 

  58. Jain, R. K., Finn, A. V., Kolodgie, F. D., Gold, H. K. & Virmani, R. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nature Clin. Pract. Cardiovasc. Med. 4, 491–502 (2007).

    Article  CAS  Google Scholar 

  59. Jain, R. K. & Carmeliet, P. F. Vessels of death or life. Sci. Am. 285, 38–45 (2001).

    Article  CAS  Google Scholar 

  60. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nature Rev. Drug Discov. 6, 273–286 (2007).

    Article  CAS  Google Scholar 

  61. Jain, R. K. Barriers to drug delivery in solid tumors. Sci. Am. 271, 58–65 (1994).

    Article  CAS  Google Scholar 

  62. Jain, R. K. & Baxter, L. T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48, 7022–7032 (1988).

    CAS  PubMed  Google Scholar 

  63. Gutmann, R. et al. Interstitial hypertension in head and neck tumors in patients: correlation with tumor size. Cancer Res. 52, 1993–1995 (1992).

    CAS  PubMed  Google Scholar 

  64. Less, J. R., Skalak, T. C., Sevick, E. M. & Jain, R. K. Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res. 51, 265–273 (1991).

    CAS  PubMed  Google Scholar 

  65. Less, J. R., Posner, M. C., Skalak, T., Wolmark, N. & Jain, R. K. Geometric resistance to blood flow and vascular network architecture in human colorectal carcinoma. Microcirculation 4, 25–33 (1997).

    Article  CAS  Google Scholar 

  66. Mouta Carreira, C. et al. LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 61, 8079–8084 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I would like to thank the clinical team leaders (T. T. Batchelor, A. G. Sorensen and C. G. Willett) and all the co-investigators of these two studies: from the Steele Lab (Y. Boucher, E. di Tomaso, D. G. Duda, K. R. Kozak, S. V. Kozin, L. L. Munn and R. Tong); from the Departments of Radiology (T. Benner, P. J. Chen, A. Fischman, S. Kalva, D. Sahani, W.-T. Zhang and M. Zhu), Radiation Oncology (M. Ancukiewicz, A. Hartford, and J. S. Loeffler), Medicine (D. Chung), Pathology (G. Lauwers, D. Louis and M. Mino-Kenudson), Surgery (P. Shellito), Haematology–Oncology (Blaszkowsky, J. Clark, K. S. Cohen, D. P. Ryan, D. T. Scadden, and A. X. Zhu) and Neurooncology (D. Cahill, J. Drappatz, M. M. Mrugala, S. Plotkin and P. Y. Wen). Many thanks to our technicians and nurses, the National Institutes of Health, the National Foundation for Cancer Research and the Montesi Family Fund for support, to all members of the Steele Lab, especially D. Fukumura and L. Xu for collaboration in the area of angiogenesis, to D. G. Duda and E. di Tomaso for their help with the manuscript preparation and to T. T. Batchelor, B. Chabner, D. G. Duda, R. Gaynor, J. S. Loeffler, J. A. Samson, A. G. Sorensen, H. D. Suit and C. G. Willett for their helpful comments on this manuscript. A special tribute goes to all the patients enrolled in these studies, and to their families and friends.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Rakesh K. Jain is at the Edwin L. Steele Laboratory for Tumour Biology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Cox-7, Boston, Massachusetts 02114, USA. jain@steele.mgh.harvard.edu,

    Rakesh K. Jain

Authors
  1. Rakesh K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

Declaration: Rakesh K. Jain is a consultant and grant recipient of AstraZeneca, a consultant of Dyax and on the scientific advisory board of SynDevRx.

Supplementary information

Supplementary information S1 (Table)

Examples of other translational trials of antiangiogenic agents (PDF 242 kb)

Related links

Related links

DATABASES

National cancer institute

breast cancer

cervical carcinoma

glioblastoma

head & neck cancer

hepatocellular carcinoma

lung cancer

melanoma

non-small cell lung cancer

ovarian cancer

pancreatic cancer

rectal cancer

renal cell carcinoma

soft tissue sarcoma

National cancer institute Drug Dictionary

bevacizumab

cediranib

sorafenib

sunitinib

FURTHER INFORMATION

Rakesh K. Jain's homepage

Genentech

HMS Promotions

Martinos Center for Biomedical Imaging

Stelle Laboratoroy

Tumour microcirculation, angiogenesis and metastasis: Biological significance and clinical relevance

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jain, R. Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nat Rev Cancer 8, 309–316 (2008). https://doi.org/10.1038/nrc2346

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2346

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing