A new class of drugs, that interferes with processes that fuel cell growth, is more effective and better tolerated that the standard-of-care drug for clear cell renal cell carcinoma (ccRCC), according to research findings published in Nature.1,2

Hypoxia-inducible factors (HIFs) allow cells to adapt to low-oxygen environments. They activate programs that support blood vessel development, facilitate oxygen delivery, and promote efficient nutrient utilization. Kidney cancer cells use this same system to continue its cell growth.

HIF-2 inhibitors downregulate the VEGF protein (a protein that helps the formation of the blood vessels tumors need to grow). However, they block VEGF in the tumor only, therefore, they do not cause cardiac toxicity or hypertension, potential effects of other VEGF inhibitors, explained James Brugarolas, MD, PhD, director of the Kidney Cancer Program at Harold C. Simmons Comprehensive Cancer Center, and senior author of the study.

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In mice transplanted with kidney cancer from more than 20 patients, HIF-2 inhibition controlled the tumors, and previous studies demonstrated HIF-2 inhibitors are safe in patients.

In this study, HIF-2 inhibition with PT2399 was compared with sunitinib, the standard or care for ccRCC. The HIF-2 inhibitor was more active and active against tumors progressing with sunitinib. In addition, metastatic kidney cancer was controlled even after 7 lines of prior therapy. These new agents also appear to be better tolerated. Mice on the HIF-2 gained weight while on the study, whereas mice on sunitinib were sickly and lost weight, a response also seen in patients taking the drug.

“HIF-2 is believed to be the most important driver of kidney cancer. Traditionally, proteins like HIF-2 were disregarded as drug targets because their shape made it nearly impossible to design drugs against them,” Brugarolas said. “The approaches we have taken pave the way for identifying drug candidates for other proteins that have traditionally been considered undruggable.”

Other cancers in which HIF-2 appears to have significant action include glioblastomas, a deadly brain cancer, and non-small cell lung cancer, the most common type of lung cancer.


1. Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist [Letter]. Nature. 2016 Sep 5. doi: 10.1038/nature19796. [Epub ahead of print]

2. New HIF-2 kidney cancer therapy more effective than current treatment, study shows [news release]. EurekAlert! web site. http://www.eurekalert.org/pub_releases/2016-09/usmc-nhk090216.php. Accessed September 13, 2016.