Combination Strategies Targeting Hypoxia Inducible Factor 1 (HIF-1) for Cancer Therapy

Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Solid tumors often present regions of decreased oxygen levels (hypoxia) due to an imbalance between increased oxygen consumption and insufficient oxygen delivery from the aberrant tumor vasculature. Intratumor hypoxia is associated with altered cellular metabolism, an invasive and metastatic phenotype, as well as resistance to radiation and chemotherapy. The discovery of Hypoxia Inducible Factor-1 (HIF-1), a transcription factor critically involved in cellular responses to hypoxia and tumor progression, has provided evidence of a potential molecular target of intratumor hypoxia that could be exploited for the development of novel cancer therapeutics. A growing number of small molecule inhibitors of HIF-1, which act by distinct molecular mechanisms, have been described so far. However, HIF-1 expression in human cancers is focal and heterogeneous, consistent with the possibility that single agent HIF-1 inhibitors may have limited clinical activity. It is then plausible that combination strategies aimed at maximizing the clinical potential of HIF-1 inhibition may be more effective.

We will discuss current approaches used for targeting HIF-1, emphasizing in particular opportunities for rationally designed combination strategies aimed at exploiting vulnerable features of the tumor microenvironment.

Keywords

Hypoxia HIF-1; Angiogenesis VEGF Cancer therapeutics Radiation therapy 

Notes

Acknowledgments

The authors would like to thank members of the Tumor Hypoxia Laboratory and Dr. R. H. Shoemaker for helpful discussion. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This research was supported in part by the Developmental Therapeutics Program, DCTD, of the National Cancer Institute, NIH.

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.DTP-Tumor Hypoxia LaboratorySAIC – Frederick, Inc., NCI at FrederickFrederickUSA

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