Non-canonical approaches to targeting hypoxic tumors.

Hypoxia is a common characteristic in solid cancers. Hypoxia-inducible factors (HIFs) are involved in various aspects of cancer, such as angiogenesis, metastasis and therapy resistance. Targeting the HIF pathway has been regarded as a challenging but promising strategy in cancer treatment with recent FDA approval of a HIF2α-inhibitor. During the past several decades, numerous efforts have been made to understand how HIFs participate in cancer development and progression along with how HIF signaling can be modulated to achieve anti-cancer effect. In this chapter, we will provide an overview of the role of hypoxia and HIFs in cancer, summarize the oxygen-dependent and independent mechanisms of HIF-1α regulation, and discuss emerging approaches targeting hypoxia and HIF signaling which possess therapeutic potential in cancer. We will emphasize on two signaling pathways, involving cyclin-dependent kinases (CDKs) and heat shock protein 90 (HSP90), which contribute to HIF-1α (and HIF-2α) stabilization in an oxygen-independent manner. Through reviewing their participation in malignant progression and the potential targeting strategies, we discuss the non-canonical approaches to target HIF signaling in cancer therapy.