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Mechanisms of Resistance to VEGF-Directed Therapy and Implications for Future Trial Design

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Renal Cell Carcinoma

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Abstract

The von Hippel–Lindau (VHL) tumor suppressor gene is functionally inactivated in the majority of renal cell carcinomas (RCC), resulting in the stabilization of hypoxia-inducible factors HIF-1 and HIF-2 and the overproduction of the angiogenesis factor VEGF. As a consequence, the microvasculature of most RCC is uniquely VEGF dependent and sensitive to drugs that block signaling through the dominant VEGF receptor, VEGFR2. The progression-free survival (PFS) of RCC patients undergoing first-line therapy with any of the recently approved VEGFR2 antagonists is nearly 1 year. Despite these encouraging results, however, the overwhelming majority of RCC patients ultimately develop resistance to these drugs. This chapter reviews several of the mechanisms by which RCC is thought to escape from VEGF-targeted therapies. Many of the proposed mechanisms of acquired resistance involve the increased production by the tumor cells of angiogenesis factors capable of compensating for the loss of VEGF function. Others involve the production of cytokines and matrix metalloproteinases by tumor-associated fibroblasts or infiltrating bone marrow-derived myeloid cells (BDMC). The chapter concludes with a brief review of ongoing clinical trials involving novel agents that could be used in combination with VEGF-targeted therapies in an effort to thwart the development of resistance.

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Authors and Affiliations

  1. Division of Oncology, Beth Israel Deaconess Medical Center, MASCO 4th Floor, 375 Longwood Avenue, Boston, MA, 02215, USA

    James W. Mier M.D.

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  1. James W. Mier M.D.
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Correspondence to James W. Mier M.D. .

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Editors and Affiliations

  1. David Geffen School of Medicine at UCLA, Department of Medicine, Cedars-Sinai Medical Center, n/a, Los Angeles, 90095, California, USA

    Robert A. Figlin

  2. Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7295, Room 21-237, 218, Chapel Hill, 27599-7295, North Carolina, USA

    W. Kimryn Rathmell

  3. Taussig Cancer Institute, Department of Solid Tumor Oncology, Cleveland Clinic, 9500 Euclid Ave, CLEVELAND, 44195-0001, Ohio, USA

    Brian I. Rini

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Mier, J.W. (2012). Mechanisms of Resistance to VEGF-Directed Therapy and Implications for Future Trial Design. In: Figlin, R., Rathmell, W., Rini, B. (eds) Renal Cell Carcinoma. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2400-0_14

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