HIF-2 Inhibitors May Be an Alternative Treatment in Renal Cell Carcinoma

A new class of agents known as HIF (hypoxia-inducible factors) -2 inhibitors may be more effective and better tolerated than sunitinib (Sutent), the current standard of care, in patients with renal cell carcinoma (RCC), according to researchers at the University Texas Southwestern Medical Center. In addition, they are now reporting in the journal Nature that it may be possible to classify RCC into HIF-2- dependent and independent tumors.

The investigators conducted a preclinical trial in mice transplanted with RCC from more than 20 patients and found that the HIF-2 inhibitor PT2399 controlled cancer in half of the tumors. Even more encouraging, they reported HIF-2 inhibitors may be more tolerable than sunitinib. In the current study, HIF-2 inhibition was able to control metastatic kidney cancer even after 7 lines of prior therapy.

“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,” said study investigator James Brugarolas, MD, PhD, Associate Professor of Internal Medicine and Director of the Kidney Cancer Program at UT Southwestern Medical Center, in a news release. “The approaches we have taken pave the way for identifying drug candidates for other proteins that have traditionally been considered undruggable.”

HIFs allow the body’s cells to adjust to low oxygen environments. HIFs activate programs that promote the development of blood vessels, facilitate oxygen delivery and promote efficient nutrient utilization.  Kidney cancer cells hijack the same system to fuel their growth.

HIF-2 inhibitors work by suppressing the effects of HIF-2, which include downregulating the VEGF protein that promotes the formation of blood vessels needed for tumor growth. However, Dr. Brugarolas said unlike existing VEGF inhibitors, HIF-2 inhibitors may block VEGF only in the cancer and therefore not cause cardiac toxicity or hypertension.

In the Nature study, researchers compared PT2399 to sunitinib head-to-head and found that the HIF-2 inhibitor was more active than sunitinib and that it was active against tumors progressing on sunitinib.  The researchers reported a subset of tumors did not respond to the drug. However, they were able to identify biomarkers that if verified could help determine which patients are more likely to benefit from HIF-2 therapies. The Texas researchers found that sensitive tumors exhibited a distinguishing gene expression signature. In addition, the sensitive tumors generally had higher HIF-2α levels.

The new findings may have implications beyond RCC. HIF-2 appears to be a significant player in other types of cancer, including glioblastomas and non-small cell lung cancer (NSCLC). Dr. Brugarolas and his colleagues hope to make HIF-2 inhibitors available to patients in the not too distant future and are currently carrying out clinical trials. In 2014, the first HIF-2 inhibitor, an oral drug known as PT2385, entered clinical trials in patients with advanced or metastatic RCC.

.