Regions of low oxygen concentration (hypoxia) within solid tumors are a prevalent feature of the cancer phenotype. Both chronic (diffusion-limited) and acute (perfusion-limited) tumor hypoxia have been described and both types of tumor hypoxia are due to abnormal aspects of tumor vasculature. The extent and magnitude of tumor hypoxia has been shown in multiple clinical studies to be a negative prognostic factor for survival. This is thought to be due to two key factors: (a) hypoxic tumor cells are able to resist conventional chemo- and radiation-therapies; and (b) hypoxic tumors are more invasive and metastatic. Transformation into a more invasive and metastatic tumor phenotype is believed to be driven by hypoxia-induced (a) genetic and epigenetic changes; (b) resistance to apoptosis; (c) induction of growth and survival factors; (d) increase in the production of extracellular matrix degrading enzymes that promote invasiveness and migration; (e) maintenance of cancer stem cell identity; (f) induction of the epithelial-mesenchymal transition (EMT); and (g) induction of angiogenesis and neovascularization. Hypoxia has also been shown to be associated with hematological malignancies and the bone marrow niches of leukemia and multiple myeloma. Hypoxic tumor cells are increasingly thought to be an attractive target for the discovery and development of novel cancer therapies; tumor hypoxia plays a central role in cancer progression and treatment resistance, and it provides a basis for selective targeting of tumor cells while sparing normoxic cells elsewhere in the body. A very promising therapeutic strategy is the use of hypoxia-activated prodrugs (HAPs), which enable the selective delivery of cytotoxic or cytostatic agents to hypoxic tumor cells. Furthermore, the development of non-invasive techniques for imaging tumor hypoxia (through PET and EPRI/MRI-based imaging approaches) will allow patient selection to identify those most likely to benefit from HAP therapy. The objective of this symposium is to provide a review of recent highlights in the study of the role of hypoxia in cancer, current advances in the discovery and development of drugs selectively targeting hypoxic cancer cells, and patient profiling approaches employing imaging or circulating or tissue biomarkers of hypoxia.
|Student / Postdoc / Fellow Member
|Student / Postdoc / Fellow Nonmember