William G. Kaelin, Jr, MD
William G. Kaelin, Jr, MD, Sidney Farber Professor of Medicine and Howard Hughes Medical Institute Investigator at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, admits that early in his research career, he and his late wife, Carolyn, would have fun speculating about winning the Nobel Prize. When Dr. Kaelin received the news on October 7 that he, Sir Peter J. Ratcliffe, FRS, FMed Sci, and Gregg L. Semenza, MD, PhD, were co-recipients of the 2019 Nobel Prize in Physiology or Medicine for their discoveries of how cells sense and adapt to oxygen availability, his reaction was joy tinged with sadness that he couldn’t celebrate the moment with Carolyn, a surgical oncologist, who died in 2015 of brain cancer unrelated to her previous diagnosis of breast cancer.
“Carolyn was a pioneering breast surgeon, and she was my best friend and hero. It was bittersweet to win the prize without her because she made everything I did possible,” said Dr. Kaelin.
Sir Peter J. Ratcliffe, FRS, FMed Sci
Gregg L. Semenza, MD, PhD
The Nobel Committee heralded the discoveries by this year’s Nobel Laureates for identifying “the mechanism for one of life’s most essential adaptive processes. They established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function. Their discoveries have also paved the way for promising new strategies to fight anemia, cancer, and many other diseases,” the committee said in its announcement.1
Discovering Cells’ Oxygen-Sensing Machinery
In 1992, Dr. Kaelin established a laboratory at Dana-Farber Cancer Institute to study how, mechanistically, mutations affecting tumor-suppressor proteins cause cancer. Those early efforts focused on defects in the von Hippel-Lindau protein (pVHL), which leads to the dominant genetic condition known as von Hippel-Lindau (VHL) syndrome. People with the defective VHL gene may experience the formation of malignant or nonmalignant tumors in many parts of the body, most commonly in the kidneys; central nervous system, including the retina; and sympathetic ganglia, including the adrenal medulla. Included among these tumors are clear cell renal cell carcinoma, hemangioblastomas, and paragangliomas, respectively.
Four years later, Dr. Kaelin discovered that cells lacking the VHL gene were incapable of sensing oxygen. He and other researchers later learned that cells lacking the VHL protein were unable to degrade hypoxia-inducible factor 1–alpha (HIF1A), which regulates genes involved in several biologic processes, including erythropoiesis and angiogenesis, and aids in the increased delivery of oxygen to the cells. The discovery of the HIF1 protein was made in 1992 by Dr. Semenza, Director, Vascular Program, Institute for Cell Engineering at Johns Hopkins University School of Medicine, and his colleagues.2 In 2001, Dr. Kaelin and Dr. Ratcliffe, Director of the Target Discovery Institute at Oxford University and Director of Clinical Research at Francis Crick Institute, independently determined how low oxygen levels keep the VHL protein from destroying HIF.
The investigations by these Nobel Laureates have implications in the treatment not only of cancer—Dr. Kaelin’s research on the VHL protein accelerated the development of vascular endothelial growth factor (VEGF) inhibitors and inspired the development of HIF2 inhibitors in the treatment of kidney cancer—but in the treatment of anemia, myocardial infarction, and stroke as well.
Drs. Kaelin, Ratcliffe, and Semenza were previously recognized for their research in oxygen sensing with the Canada Gairdner International Award in 2010 and the Albert Lasker Basic Medical Research Award in 2016. In 2016, Dr. Kaelin was also the recipient of ASCO’s Science of Oncology Award and Lecture for his groundbreaking research in VHL.
Two weeks after being awarded the Nobel Prize, Dr. Kaelin talked with The ASCO Post about his research in VHL and how the Nobel Prize may help raise awareness of the importance of investigator-initiated, curiosity-driven, fundamental research in cancer.
A Team Effort
First, congratulations on receiving this prestigious award. What does this recognition mean to you personally and professionally?
The first thing I’m learning is that 2 weeks isn’t enough time to absorb what just happened and what the implications may be. The one thing I have felt from the moment I got the good news is how thrilled I am to share this award with the people who made it possible, including my family, friends, colleagues, mentor David Livingston, MD [Deputy Director of the Dana-Farber/Harvard Cancer Center], as well as the many very talented trainees who have worked in my laboratory. It has been so much fun to share this award with them and to see the joy on their faces. Seeing how happy it has made them makes me extremely happy, because achieving this award was a team effort.
Finding Clues in VHL Disease
Please talk about how oxygen levels affect cell function and cause the development of cancer.
My line of investigation, as opposed to that of my fellow awardees, started by studying VHL disease. What was striking to me is that the tumors that develop in VHL disease are notoriously rich in blood vessels, and they occasionally stimulate red blood cell production. Both of those effects are responses you might see, for example, if a tissue wasn’t getting enough oxygen, and it was trying to increase oxygen delivery and oxygen-carrying capacity. That was the clue that maybe the VHL gene and the protein it encoded were critical for oxygen sensing, and we thought it was important to understand oxygen sensing.
It was known that people who are born with a defective copy of the VHL gene and have VHL disease are at an increased risk of developing kidney cancer. Both the maternal and paternal copies of the VHL gene are also mutated or lost in many sporadic kidney cancers. Here, the mutations occur somatically, in contrast to VHL disease, where the first mutation is in the germline.
FIGURE 1: When oxygen levels are hypoxic, HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4). Illustration: © The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén.
What happens in these kidney cancers is that the tumors co-opt the oxygen-sensing pathway. We came to learn that a major job of the VHL protein is to regulate the levels of HIF. And for reasons that are only partially understood, at least in the cells that are capable of becoming kidney cancers, deregulation of HIF2 contributes to the development of those tumors. We know that HIF2 in the context of kidney cancer can both increase cellular proliferation and also induce angiogenesis, helping the tumors to obtain a blood supply.
Deregulation of HIF2 and Other Cancers
Are there other types of cancers affected by the deregulation of HIF2?
Patients with VHL disease are also at an increased risk for paragangliomas (when these tumors arise in the adrenal gland, they are considered pheochromocytomas). Patients with VHL disease can also develop hemangioblastomas, typically of the cerebellum, retina, and spinal cord. We strongly suspect that HIF2 plays a role in the development of these tumors as well, but the evidence is not quite as clear as it is for kidney cancer.
I should point out that nearly every cell in the body is capable of expressing HIF1, the more famous member of the HIF family, whereas expression of HIF2 is much more restricted. There are a lot of cell types that do not express HIF2. Then the question is, are there cancers being driven by HIF1? I would say the jury is still out.
How Cells Respond to Changes in Their Environment
You, Dr. Semenza, and Sir -Radcliffe were also co-recipients of the 2016 Albert Lasker Basic Research Award for your discovery of the pathway by which cells sense and adapt to changes in oxygen availability. Did you collaborate on this research?
I would say that we were friendly competitors. I never formally collaborated with them, but we were certainly reading each other’s scientific papers. And just as you would hope happens in science, I would read one of their papers, and it would help us get to the next step in our research; in turn, they would read one of our papers, which accelerated their research.
What was quite exhilarating was around 1999, our line of investigation, which began with the study of VHL, collided with their research in trying to understand the regulation of the hormone erythropoietin (EPO), which had become the one canonical example of a so-called hypoxia-inducible gene. They had identified HIF as the regulator of EPO and were trying to understand the regulation of HIF. We were trying to understand how VHL linked to oxygen sensing. When our lines of investigation collided in 1999, our research and Peter’s research progressed rapidly. Over the next 2 years, we worked out the actual modification of HIF that rendered its abundance oxygen-sensitive, which was mainly prolyl hydroxylation.
At that point, the three of us were somewhat joined at the hip. We were co-recipients of the 2010 Canada Gairdner International Award and, in 2016, of the Lasker Award for Basic Medical Research, which are sometimes referred to as the pre–Nobel Prizes. I assumed we might be in the conversation for the Nobel Prize, but you never want to get your hopes up too much.
Finding the Rosetta Stone for Kidney Cancer
How might the Nobel Prize affect your future research?
I don’t think the thrust of my research is going to change. One of the reasons I decided to work on VHL disease in 1993 was because, at the time, the molecular insights being made into cancer using molecular biology and modern genetics almost always seemed to involve a cancer that was fascinating, but numerically not very important. Also, in the 1980s, I was a house officer and Chief Resident in Internal Medicine at Johns Hopkins Hospital. There was a brilliant, young faculty member there named Bert Vogelstein [Clayton Professor of Oncology and Pathology at Johns Hopkins Medicine], who was overturning the existing dogma that you couldn’t study solid tumors using modern molecular techniques.
I thought if we were ever going to make real headway in cancer mortality, we needed to go after the big bad epithelial cancers, including breast, colon, lung, and kidney. VHL disease was an important experiment of nature, telling us that the VHL gene could be the Rosetta Stone for studying kidney cancer.
In the late 1980s and early 1990s, kidney cancer was very difficult to treat, because it wasn’t particularly sensitive to radiation or any forms of chemotherapy. I thought, let’s use the VHL gene to see if we could deconstruct a common epithelial cancer and use that information to develop new targeted agents. Then, let’s develop effective drug combinations, because I think the answer for any of these complex cancers is to have combinations of active agents to avoid drug resistance.
My laboratory is still focused on looking at the way cells sense and respond to oxygen, in identifying new targets in kidney cancer, and in laying the groundwork for combination therapy. I’m thrilled, no thanks to me, that we now have immune checkpoint inhibitors that may have a role in the management of kidney cancer. Today, we think the standard front-line therapy for this cancer might include a checkpoint inhibitor plus a VEGF inhibitor. However, now, you can imagine using an HIF2 inhibitor as part of this mix and perhaps start to imagine other targets in kidney cancer that are being identified from our research and the research of others.
VHL disease was an important experiment of nature, telling us that the VHL gene could be the Rosetta Stone for studying kidney cancer.— William G. Kaelin, Jr, MD
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So, I am hopeful that, before I retire, we will have three and four combinations of agents that will take us from transient responses to durable remissions in kidney cancer, and, in time, maybe even a cure. That is one focus of my research. I have also become increasingly interested in converting undruggable targets into druggable targets. Our group was among those that discovered the mechanism of action of thalidomide-like drugs in the treatment of multiple myeloma. That has completely opened my eyes to the fact that, in some cases, we can drug undruggable proteins, including transcription factors, by simply targeting them for proteasomal activation. My lab is developing new screening assays to make it easier to identify the next chemical/drug that will destabilize undruggable oncoproteins.
I have been very fortunate over the years to attract extremely dedicated and talented trainees to my lab, many of whom have gone on to develop their own successful laboratory programs. Having the Nobel Prize will help us to continue to attract outstanding young people.
I also hope to lend my voice to those who champion investigator-initiated, curiosity-driven, fundamental research, because real translation happens when there are people doing the kind of mechanistic work that gives us the knowledge to actually intervene in a rational way and to develop more effective therapies for cancer. ■
DISCLOSURE: Dr. Kaelin has served in a leadership role for Lilly Pharmaceuticals; owns stock or other ownership interests in Agios, Cedilla Therapeutics, FibroGen, Infinity Pharmaceuticals, Lilly, Peloton Therapeutics, Tango Therapeutics, and TRACON Pharma; has served as a consultant or advisor to Agios, Cedilla Therapeutics, FibroGen, Nextech Invest, Peloton Therapeutics, Tango Therapeutics, and TRACON Pharma; holds patents and receives royalties through the Dana-Farber Cancer Institute; and has been reimbursed for travel, accommodations, or other expenses by FibroGen, Lilly, Nextech Invest, Peloton Therapeutics, and TRACON Pharma.
1. The Nobel Prize in Physiology or Medicine 2019. Available at www.nobelprize.org/prizes/medicine/2019/press-release/. Accessed November 8, 2019.
2. Johns Hopkins Medicine: Gregg L. Semenza, MD, PhD. Available at www.hopkinsmedicine.org/research/about-faculty/awards/lasker/. Accessed November 8, 2019.