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Hypoxia inducible factor-1 as a cancer drug target

¹ Arizona Cancer Center, University of Arizona, Tucson, Arizona and ² ProlX Pharmaceuticals, Tucson, Arizona

Requests for Reprints: Garth Powis, Arizona Cancer Center, University of Arizona, Room 3977, 1515 North Campbell Avenue, Tucson, AZ 85724-5024. Phone: (520) 626-6408; Fax: (520) 626-4848. E-mail: gpowis{at}azcc.arizona.edu

The hypoxia inducible factor 1 (HIF-1) is a heterodimeric transcription factor that is an important regulator of the growing tumor's response to hypoxia. HIF-1 activity in tumors depends on the availability of the HIF-1 subunit, the levels of which increase under hypoxic conditions and through the activation of oncogenes and/or inactivation of tumor suppressor genes. HIF-1 activates genes that allow the cancer cell to survive and grow in the hostile hypoxic tumor environment. Increased tumor HIF-1 has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to the current interest in HIF-1 as a cancer drug target. A number of anticancer agents have been reported to decrease HIF-1 or HIF-1 transactivating activity in cells in culture. However, more relevant to the agents' antitumor activity is whether HIF-1 is inhibited in tumors in vivo. This has been demonstrated for only a few of the reported HIF-1 inhibitors. Some of the agents are moving toward clinical trial where it will be important to demonstrate that the agents inhibit HIF-1 in patient tumors or, failing this, the downstream consequences of HIF-1 inhibition such as decreased vascular endothelial growth factor formation, and relate this inhibition to antitumor activity. Only in this way will it be possible to determine if HIF-1 is a valid cancer drug target in humans.

Key Words: HIF-1 • hypoxia • cancer treatment

Grant support: Supported in part by CA CA052995 and CA098920.

Received 2/ 4/04; revised 3/19/04; accepted 3/22/04.