NCI Support for Basic Science Paves Way for Kidney Cancer Drug Belzutifan
Posted on by Norman "Ned" Sharpless, M.D., National Cancer Institute
There’s exciting news for people with von Hippel-Lindau (VHL) disease, a rare genetic disorder that can lead to cancerous and non-cancerous tumors in multiple organs, including the brain, spinal cord, kidney, and pancreas. In August 2021, the U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg), a new drug that has been shown in a clinical trial led by National Cancer Institute (NCI) researchers to shrink some tumors associated with VHL disease , which is caused by inherited mutations in the VHL tumor suppressor gene.
As exciting as this news is, relatively few people have this rare disease. The greater public health implication of this advancement is for people with sporadic, or non-inherited, clear cell kidney cancer, which is by far the most common subtype of kidney cancer, with more than 70,000 cases and about 14,000 deaths per year. Most cases of sporadic clear cell kidney cancer are caused by spontaneous mutations in the VHL gene.
This advancement is also a great story of how decades of support for basic science through NCI’s scientists in the NIH Intramural Research Program and its grantees through extramural research funding has led to direct patient benefit. And it’s a reminder that we never know where basic science discoveries might lead.
Belzutifan works by disrupting the process by which the loss of VHL in a tumor turns on a series of molecular processes. These processes involve the hypoxia-inducible factor (HIF) transcription factor and one of its subunits, HIF-2α, that lead to tumor formation.
The unraveling of the complex relationship among VHL, the HIF pathway, and cancer progression began in 1984, when Bert Zbar, Laboratory of Immunobiology, NCI-Frederick; and Marston Linehan, NCI’s Urologic Oncology Branch, set out to find the gene responsible for clear cell kidney cancer. At the time, there were no effective treatments for advanced kidney cancer, and 80 percent of patients died within two years.
Zbar and Linehan started by studying patients with sporadic clear cell kidney cancer, but then turned their focus to investigations of people affected with VHL disease, which predisposes a person to developing clear cell kidney cancer. By studying the patients and the genetic patterns of tumors collected from these patients, the researchers hypothesized that they could find genes responsible for kidney cancer.
Linehan established a clinical program at NIH to study and manage VHL patients, which facilitated the genetic studies. It took nearly a decade, but, in 1993, Linehan, Zbar, and Michael Lerman, NCI-Frederick, identified the VHL gene, which is mutated in people with VHL disease. They soon discovered that tumors from patients with sporadic clear cell kidney cancer also have mutations in this gene.
Subsequently, with NCI support, William G. Kaelin Jr., Dana-Farber Cancer Institute, Boston, discovered that VHL is a tumor suppressor gene that, when inactivated, leads to the accumulation of HIF.
Another NCI grantee, Gregg L. Semenza, Johns Hopkins School of Medicine, Baltimore, identified HIF as a transcription factor. And Peter Ratcliffe, University of Oxford, United Kingdom, discovered that HIF plays a role in blood vessel development and tumor growth.
Kaelin and Ratcliffe simultaneously showed that the VHL protein tags a subunit of HIF for destruction when oxygen levels are high. These results collectively answered a very old question in cell biology: How do cells sense the intracellular level of oxygen?
Subsequent studies by Kaelin, with NCI’s Richard Klausner and Linehan, revealed the critical role of HIF in promoting the growth of clear cell kidney cancer. This work ultimately focused on one member of the HIF family, the HIF-2α subunit, as the key mediator of clear cell kidney cancer growth.
The fundamental work of Kaelin, Semenza, and Ratcliffe earned them the 2019 Nobel Prize in Physiology or Medicine. It also paved the way for drug discovery efforts that target numerous points in the pathway leading to clear cell kidney cancer, including directly targeting the transcriptional activity of HIF-2α with belzutifan.
Clinical trials of belzutifan, including several supported by NCI, demonstrated potent anti-cancer activity in VHL-associated kidney cancer, as well as other VHL-associated tumors, leading to the aforementioned recent FDA approval. This is an important development for patients with VHL disease, providing a first-in-class therapy that is effective and well-tolerated.
We believe this is only the beginning for belzutifan’s use in patients with cancer. A number of trials are now studying the effectiveness of belzutifan for sporadic clear cell kidney cancer. A phase 3 trial is ongoing, for example, to look at the effectiveness of belzutifan in treating people with advanced kidney cancer. And promising results from a phase 2 study show that belzutifan, in combination with cabozantinib, a widely used agent to treat kidney cancer, shrinks tumors in patients previously treated for metastatic clear cell kidney cancer .
This is a great scientific story. It shows how studies of familial cancer and basic cell biology lead to effective new therapies that can directly benefit patients. I’m proud that NCI’s support for basic science, both intramurally and extramurally, is making possible many of the discoveries leading to more effective treatments for people with cancer.
 Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R; MK-6482-004 Investigators. N Engl J Med. 2021 Nov 25;385(22):2036-2046.
 Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). Choueiri TK et al. J Clin Oncol. 2021 Feb 20;39(6_suppl): 272-272.
Von Hippel-Lindau Disease (Genetic and Rare Diseases Information Center/National Center for Advancing Translational Sciences/NIH)
Clear Cell Renal Cell Carcinoma (National Cancer Institute/NIH)
Belzutifan Approved to Treat Tumors Linked to Inherited Disorder VHL, Cancer Currents Blog, National Cancer Institute, September 21, 2021.
The Long Road to Understanding Kidney Cancer (Intramural Research Program/NIH)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s institutes and centers to contribute occasional guest posts to the blog as a way to highlight some of the cool science that they support and conduct. This is the first in the series of NIH institute and center guest posts that will run until a new permanent NIH director is in place.]
Thanks for this interesting communication. I hope this important news is also valid for the ocular manifestations of VHL disease: a serious clinical problem, as reported in several studies.
– Singh AD, Shields CL, Shields JA. von Hippel-Lindau disease. Surv Ophthalmol. 2001 Sep-Oct;46(2):117-42. doi: 10.1016/s0039-6257(01)00245-4. PMID: 11578646.
“.. Retinal capillary hemangioma is the most common manifestation of VHL disease and, therefore, ophthalmologists are frequently involved in the care of patients with this disease…”
– Pilotto E, Midena G, Torresin T, De Mojà G, Bacelle ML, Ferrara AM, Zovato S, Midena E. Retinal Glial Cells in Von Hippel-Lindau Disease: A Novel Approach in the Pathophysiology of Retinal Hemangioblastoma. Cancers (Basel). 2021 Dec 30;14(1):170. doi: 10.3390/cancers14010170. PMID: 35008334; PMCID: PMC8750586.
“..At the retinal level, VHL protein is able to regulate tumor growth, angiogenic factors, and neuroinflammation, probably stimulating retinal glial cells…”
– Goswami A, Surve A, Venkatesh P. Optical Coherence Tomography Angiography of Early Stage 1a Retinal Hemangioblastoma in Von-Hippel-Lindau. J Kidney Cancer VHL. 2021 Sep 23;8(3):15-18. doi: 10.15586/jkcvhl.v8i3.158. PMID: 34631390; PMCID: PMC8476344.
“.. focal vasoproliferative tumors of retinal capillaries called retinal capillary hemangioblastomas (RCH). These tumors are initially small and can be easily missed if not looked for carefully. As they grow, these tumors are more demanding to treat and hence the importance of detecting them early and treating them…”
Furthermore, would it be useful to add in some patients treated with Belzutifan also the Hyperbaric Oxygen Therapy ?
So fascinating how research aimed at helping people with a rare disease can end up helping folks suffering from more common diseases. Keep up the good work!
Many years ago I visited a 50 year old man:
he had a conspicuous angioma (Nevus Flammeus) on the same side of the face where the eye was affected by glaucoma, while the contralateral eye was almost normal. In the event that it was Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis Syndrome), I requested MRI of the brain, which was found to be normal; the Abdomen Ultrasound was also normal. The patient was in good general health for many years, with good clinical course of ocular disease; he then fell ill with lymphoma, but responded well to treatment and managed to overcome this unfortunate event. After a couple of years, he reports to me that he is being checked for a questionable aspect of a kidney.
I have presented this case to emphasize that the individual can have characteristics that go beyond the schematic classifications of individual diseases; this patient was without eye lesions typical of VHL disease, but with some traits that could be part of it.
What role does epigenetics play in leading to the expression of pathological traits in the various parts of the body? There are many things to discover about it.
In the meantime, we welcome the studies that already indicate good results using Belzutifan in the ocular localizations of VHL disease.
Henry Wiley, Hanna R. Coleman, Eric Jonasch, Ramaprasad Srinivasan, Frede Donskov, Anders Kruse, Jodi K. Maranchie, Jay Chhablani, Tobias Else, Hakan Demirci, Benjamin L. Maughan, Mary Elizabeth Hartnett, Rodolfo F. Perini, Eric K. Park, Emily Y Chew;
Oral HIF-2α inhibitor belzutifan for ocular von Hippel-Lindau (VHL) disease. Invest. Ophthalmol. Vis. Sci. 2021;62(8):32.
Unfortunately, a lot of people suffer from various severe diseases and no one is immune from this. It is indisputable fact that most often we don’t have medicine for such awful diseases, including cancerous tumors, but your news was able to blow my mind because it is so incredible that the new drug “Belzutifan (Welireg)” was approved by the U.S. Food and Drug Administration (FDA). I think that it can simply turn the history around and it can totally change the lives of many people who have von Hippel-Lindau (VHL) disease. Of course, it is not such a widespread disease, but I know that it is serious to a global extent and that it is a lifelong condition which is not so easy to cope with. I really hope that this drug will have a huge unsurpassed effect and that we can see a great breakthrough when a lot of people will live a fulfilling life without a great deal of agony.
Definitely it’s a blessing for them who are suffering.Keep doing hard work for Mankind.