From the Tumor Hypoxia Laboratory, Developmental Therapeutics Program, SAIC Frederick, Inc. and the National Cancer Institute, Frederick, Frederick, MD
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Giovanni Melillo, MD, Tumor Hypoxia Laboratory, Bldg 432, Rm 218, National Cancer Institute, Frederick, MD 21702-1201; E-mail: melillog{at}ncifcrf.gov
Overview: Hypoxia, a decrease in oxygen levels, is a hallmark of solid tumors. Adaptation of tumor cells to low oxygen concentration is associated with resistance to therapy and decreased survival of patients with cancer. If these features contribute to the malignant phenotype, they may offer a unique opportunity for selective therapeutic approaches by targeting pathways essential for cancer cell survival in hypoxia. In the last two decades, the discovery of hypoxia-inducible factors (HIF), a family of transcription factors crucially involved in the response of mammalian cells to low oxygen concentration, has led to the identification of a molecular target associated with hypoxia for the development of novel cancer therapeutics.
Early controversy as to whether HIF-1 is a good target for therapy has not discouraged academic groups and pharmaceutical companies from actively engaging in the discovery of small molecule inhibitors of HIF-1. The exponentially growing interest in therapeutic strategies that target hypoxia/HIF-1 will generate more active compounds of potential interest for preclinical and clinical development. Identification and validation of pharmacodynamic endpoints relevant to the HIF-1 pathway are essential for a rapid translation of these agents to the treatment of human cancers. Integration of these biomarkers in early clinical trials may provide valuable information to determine the contribution of HIF-1 inhibitors to therapy response. HIF-1 inhibitors should be incorporated in combination strategies to effectively target multiple cellular components of the tumor microenvironment and redundant signaling pathways frequently deregulated in human cancer.
