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Gregg Semenza, MD, PhD: The Role of HIF-1 and HIF-2 in Cancer

Gregg Semenza, MD, PhD.

Gregg L. Semenza, MD, PhD, was recently awarded the Nobel Prize in Physiology or Medicine for his groundbreaking work in isolating hypoxia inducible factor (HIF) 1, which controls genes that are involved in cells' adaptation to low oxygen levels, with implications for cancer, ischemia, and chronic lung disease. In this interview with i3 Health, Dr. Semenza discusses the involvement of HIF-1 and HIF-2 in cancer and shares insights on the progress that is being made in developing HIF-1 and HIF-2 inhibitors as potential cancer treatments.

What role does HIF-1 play in cancer?

Gregg L. Semenza, MD, PhD: HIF-1 plays an important role in the vascularization of many tumors, the regulation of tumor metabolism, invasion and metastasis, maintenance of cancer stem cells, evasion of anti-tumor immunity, and resistance to radiation and chemotherapy. We view high expression of HIF-1, HIF-2, or both as representing the lethal cancer phenotype, and we believe that HIF inhibitors may improve outcomes when added to existing therapeutic regimens.

In what cancers have HIF inhibitors come the furthest in terms of drug development? How close are these drugs to reaching the clinic?

Dr. Semenza: A phase 1 trial of the selective HIF-2 inhibitor PT2385 in patients with renal cell carcinoma (RCC) was reported in 2018. Even though phase 1 trials are designed to demonstrate drug safety rather than efficacy, among 50 patients with advanced RCC who had failed multiple therapies, there was one complete response, in addition to multiple patients with a partial response or stable disease. Phase 2 trials are now underway.

What ongoing or planned investigations do you have that are related to HIF in cancer?

Dr. Semenza: We have an active drug discovery program in my laboratory. We have identified compounds that inhibit both HIF-1 and HIF-2 and block tumor growth in mouse models. We are screening multiple cancer types in mouse models in order to identify those cancers that seem most likely to respond to these HIF inhibitors, either alone or in combination with current therapies.

From a more general perspective, how do you see the treatment of cancer evolving in the future?

Dr. Semenza: The key to effective cancer therapy will be the identification of combination drug therapy that is both safe and efficacious for each individual cancer patient and which, whenever possible, restores the ability of the immune system to kill cancer cells.

About Dr. Semenza

Gregg L. Semenza, MD, PhD, is the C. Michael Armstrong Professor of Genetic Medicine, Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry at the Johns Hopkins University School of Medicine. He is a member of the Institute for Cell Engineering, the McKusick-Nathans Institute of Genetic Medicine, and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. A founding fellow of the American College of Medical Genetics, he has been elected to the Association of American Physicians and the National Academy of Sciences. He is Deputy Editor of the Journal of Clinical Investigation and serves on the editorial board of several journals. In addition to being one of three recipients of the 2019 Nobel Prize in Physiology or Medicine, Dr. Semenza has been recognized with the Lefoulon-Delalande Grand Prize from the Institut de France, the Gairdner Award, the Stanley J. Korsmeyer Award, the E. Mead Johnson Award for Research in Pediatrics, the Jean and Nicholas Leone Award from the Children's Brain Tumor Foundation, the Established Investigator Award from the American Heart Association, and the Lucille P. Markey Scholar Award in Biomedical Science.

For More Information

Semenza GL (2019). Pharmacologic targeting of hypoxia-inducible factors. Annu Rev Pharmacol Toxicol, 59:379-403. DOI:10.1146/annurev-pharmtox-010818-021637

Courtney KD, Infante JR, Lam ET, et al (2018). Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol, 36(9):867-874. DOI:10.1200/JCO.2017.74.2627

Image courtesy of Johns Hopkins Medicine.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.

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