Abstract
The hypoxic phenotype, characterized by a variety of adaptations that cells make to low oxygen conditions, is a hallmark of solid tumors that serves as both a major challenge and a substantial opportunity in the treatment of cancer. These adaptations influence a wide range of cellular processes, including cell cycle, metabolism, oxygen delivery, proliferation, energy production, differentiation, replication, and sensitivity to growth and death signals. From a clinical perspective, the hypoxic phenotype results in more aggressive tumors that exhibit greater resistance to chemotherapy and radiation therapy and enhanced propensity to metastasize. At the cellular and molecular level, many of the adaptations to hypoxia are mediated by a single transcription factor, the hypoxia-inducible factor (HIF). HIF is predominantly regulated by the von Hippel–Lindau (VHL) tumor suppressor gene. Mutation of VHL results in constitutive activation of HIF and a pseudo-hypoxic phenotype. Here, we review efforts to target either VHL or the hypoxic phenotype to identify pathways and agents as potential cancer therapeutics. Particular focus is given to distinguish between HIF-dependent and HIF-independent therapies.
Raymond J. Louie and Mercè Padró contributed equally to this work.
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Louie, R., Padró, M., Giaccia, A., Chan, D. (2014). Small Molecules Targeting the VHL/Hypoxic Phenotype. In: Melillo, G. (eds) Hypoxia and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9167-5_11
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DOI: https://doi.org/10.1007/978-1-4614-9167-5_11
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