Scientific review focuses on hypoxia-inducible factors
The biochemical mechanisms that control the stabilization of hypoxia-inducible factors (HIFs) and the molecular strategies that can be exploited pharmacologically to promote or inhibit HIFs are the focus of a new scientific review published by faculty in the Department of Anesthesiology, Critical Care and Pain Medicine and the Department of Emergency Medicine.
“Targeting hypoxia-inducible factors: Therapeutic opportunities and challenges” was published in the Dec. 20 issue of Nature Reviews Drug Discovery.
Co-authored by Xiaoyi Yuan, PhD, and Wei Ruan, MD, PhD, both assistant professors of anesthesiology, this scientific review describes the molecular mechanism controlling the transcriptional activity of HIFs. It highlights pharmacological opportunities that promote the stabilization of HIFs or inhibit their functional activity.
From their first discovery in the early 1990s, HIF activation or inhibition has evolved into FDA-approved therapeutic approaches in different human diseases. HIFs are stabilized during inflammatory conditions or cancer – resulting in opportunities for targeting HIFs for therapy.
The authors discuss the usefulness of pharmacological stabilization of HIFs (named HIF-PHD inhibitors) to treat renal anemia, inflammatory diseases, or ischemia-reperfusion injury. For example, co-author Ben Bobrow, MD, is currently leading a randomized clinical trial using a HIF-PHD inhibitor to treat lung inflammation in patients with acute respiratory distress syndrome (ARDS) at UTHealth Houston, in collaboration with the Department of Anesthesiology, Critical Care and Pain Medicine.
The article also focuses on HIF inhibitors for the treatment of cancers and other emerging indications. Finally, they review specific challenges to using HIF activators or inhibitors in patients and provide an outlook on the future opportunities and potential limitations for targeting hypoxia signaling pharmacologically.
“Promoting HIF stabilization has been implicated in benefiting ischemia and reperfusion injury of the heart and liver, acute kidney injury, ARDS, inflammatory bowel disease, infections with pathogens, hemorrhagic shock, and renal anemia,” wrote the authors. “Similar advancements also have been made in developing novel pharmacologic compounds that prevent the activation of HIF-dependent gene transcription, particularly for treating different types of cancers.”
Researchers noted that HIF-PHD inhibitors have shown an excellent short-term safety record in large phase-3 clinical trials and were not associated with serious side effects. These findings encourage further clinical studies of HIF-PHD inhibitors for acute treatment indications, such as preventing perioperative organ injuries, including acute kidney injury, myocardial injury, or ARDS. Further studies will be needed to confirm long-term safety, outcomes, and optimal dosing strategy of HIF-PHD inhibitors in different patient populations, such as the critically ill.
“Much future work will be required to determine how to optimally utilize these compounds for additional disease conditions or other potential pharmacologic strategies for specific targeting,” wrote the authors. “Developing specific delivery mechanisms is another important direction for developing HIF activators or inhibitors in the future.”
UTHealth Houston co-authors include Holger Eltzschig, MD, PhD, chair of the Department of Anesthesiology, Critical Care, and Pain Medicine; and Bentley Bobrow, MD, chair of the Department of Emergency Medicine. Peter Carmeliet, MD, PhD, Aarhus University in Denmark, also contributed.