How Researchers Harnessed the Momentum of Discovery to Create a New Kidney Cancer Drug

Countless medical innovations are born in academic laboratories.

History bears this out: penicillin, one of the world's first antibiotics that revolutionized modern medicine; vaccines, from conventional ones that eliminated scourges like polio, measles, and others, to next-generation versions deployed during the COVID-19 pandemic; cholesterol-lowering agents, known as statins, that have transformed the treatment of heart disease; drugs that block the proteins PD-1 and PD-L1 and "wake up" the immune system, opening up a whole new approach to treating multiple types of cancer; and even the new GLP-1 receptor agonists, a novel class of drugs that are now remaking how doctors treat obesity and type 2 diabetes.

Just as basic science discoveries have helped give rise to these and many other remarkable medicines, they are also propelling powerful new therapies for kidney cancer.

In December 2023, the U.S. Food and Drug Administration (FDA) approved the drug belzutifan for forms of kidney cancer — a clinical milestone that was years in the making, and one made possible in part by the trailblazing investigations of Dana-Farber's William G. Kaelin Jr., MD, and his colleagues. Kaelin, along with two other scientists, was awarded the 2019 Nobel Prize in Physiology or Medicine for his contributions to uncovering the molecular basis of how cells sense changes in oxygen levels.

Through his foundational work, he helped reveal the key molecular players that enable cells to sense and adapt to shifts in oxygen availability, including a powerful molecular switch involving a protein known as HIF2a. In kidney cancer cells, this switch is essentially stuck in the "on" position, making the cells believe they are hypoxic. This perceived need for oxygen drives the growth of new blood vessels as well as other tumor-promoting activities. Belzutifan inhibits the HIF2a protein and therefore blocks these actions.

"I point out to my students that there's a lot of luck involved in winning a Nobel Prize and it's also inherently subjective," said Kaelin. "But drug approvals are far more meaningful and far more objective. The fact that the knowledge we generated made predictions that turned out to be true and demonstrably helped patients in phase three clinical trials — that's the real prize."

Building Blocks of Innovation

The science that lays the groundwork for an FDA-approved drug is a lot like masonry. Individual discoveries emerge like bricks, each contributed by a team of researchers working as part of a broader community of scientists. Different teams lay different bricks, which rest on those that came before. Eventually, these bricks coalesce to form a sturdy and recognizable structure — the evidence base needed to justify the rigorous clinical trials that will help test if a novel drug is safe and effective for patients.

Structures do not get built overnight. One of the critical bricks leading to the clinical approval of belzutifan was placed in the early 1990's. Kaelin was launching his own laboratory as an investigator at Dana-Farber just down the hall from his mentor, David Livingston, MD, a renowned cancer researcher who led pioneering studies of tumor suppressor genes, including RB1 as well as BRCA1 and BRCA2. Livingston passed away in 2021.

"People appropriately whispered in my ear that eventually I should develop my own scientific identity, which meant that I probably needed to start working on something different than what David was working on," said Kaelin. He read a journal article that described a newly identified tumor-suppressor gene called VHL, short for von Hippel-Lindau syndrome, which is a rare, inherited disorder caused by mutations in the eponymous gene that cripple its activity. Patients with this syndrome often develop benign tumors in various parts of the body. They also are at high risk of certain cancers, including the most common form of kidney cancer, which is called clear cell renal cell carcinoma (ccRCC).

"This is where my clinical training was helpful, in addition to my scientific training," said Kaelin. "I knew that kidney cancer was common in the developed world, and I thought, with everything else being equal, it was better to work on a common cancer than an uncommon one — as most of the progress that was being made back then in molecular oncology was in relatively rare and admittedly relatively simple cancers."

VHL Gene Is Key to Kidney Cancer

Kaelin set out to learn more about the biology of the VHL gene. He knew that the tumors in von Hippel-Lindau syndrome frequently induce the formation of new blood vessels because they produce high levels of a blood vessel growth factor called VEGF, and that they can also produce high levels of erythropoietin, a hormone that stimulates the production of red blood cells in response to low oxygen levels ("hypoxia"). Together, these bits of information suggested VHL might play a role in sensing oxygen because VEGF and erythropoietin are normally activated when tissues are starved of oxygen.

More definitive proof came from a set of experiments that Kaelin and his colleagues published in 1996. As they suspected, cells that lacked a normal copy of the VHL gene seemed as if they were starved of oxygen regardless of how much oxygen was present. For example, they produced lots of VEGF even when oxygen was plentiful. But in cells in which VHL function had been restored, VEGF was only produced under hypoxic conditions.

"Someone called this the 'first harpoon in the whale,' because now we knew our hypothesis was correct — you needed the VHL gene to sense oxygen — and knew we could dissect the oxygen-sensing mechanism in the laboratory using these cells that did or did not contain VHL," recalled Kaelin.

The VHL gene contains the instructions for making the VHL protein. In parallel, his lab, as well as other research teams, were on the hunt for other cellular proteins that interact with the VHL protein. They discovered something surprising about how the VHL protein works: It is part of a vast cellular recycling system that flags certain proteins for destruction. In 2000, they published their findings in the journal Nature Cell Biology, identifying HIF2a as one such protein.

"Several other labs reached this same conclusion quickly after us," said Kaelin. "And so, the race was on to understand how this was being regulated by oxygen."

The answer came about a year later. In a set of back-to-back papers published in 2001 in the journal Science, Kaelin's team — and another led by Peter Ratcliffe, a co-recipient of the 2019 Nobel Prize — revealed the molecular basis of how cells perceive changes in oxygen levels.

It unfolds like this: When oxygen is sufficiently abundant, a special chemical tag called a hydroxy group is added to certain building blocks within the HIF2a protein. This tag allows VHL to grab on and mark the protein for subsequent degradation. But when oxygen is scarce, the hydroxy group is not added, which means VHL cannot bind and HIF2a persists. HIF2a is a so-called "transcription factor" — a type of protein that controls the activity of downstream genes. HIF2a turns on many genes that help cells cope with hypoxia, such as VEGF and erythropoietin, much as a conductor oversees an orchestra.

Belzutifan's Impact on Patient Care

By painting this molecular picture of how cells sense and respond to oxygen levels, Kaelin and his colleagues sparked news ways of thinking about — and ultimately attacking — cancer, including kidney cancer.