William G. Kaelin, Jr., MD, of Dana-Farber Cancer Institute, won a Nobel Prize in Medicine on Oct. 7 for deciphering the mechanism that enables cells to sense and adapt to changes in oxygen abundance.
What are the most important applications of this amazing discovery that can change the route of applied science?
We now understand the molecular pathway used to sense oxygen and to adapt by activating hypoxia-inducible genes involved in processes such as angiogenesis, red blood cell formation, and metabolism. What is exciting is that there are several places one can intervene to make the pathway more active or less active. For example, we now have new drugs that stabilize HIF, which might be useful for diseases like anemia, heart attack, and stroke, where oxygen delivery is a problem. Conversely, blocking the pathway, such as with HIF-2 inhibitors, looks like a promising way to treat kidney cancer and I am hopeful that HIF-1 inhibitors might also be useful for certain cancers.
Do you think HIF-2 inhibitors have the potential to be effective in other subtypes of hypoxic tumors other than kidney cancer?
We know from studies of VHL disease patients that VHL mutations also predispose to some other tumors including paragangliomas and hemangioblastomas. In laboratory mice, genetic ablation of HIF-2 prevents the development of blood vessel tumors that loosely resemble hemangioblastomas. So I am hopefully that HIF-2 will be helpful for those tumors.
We also know that some paragangliomas that don’t have a VHL mutation have other mutations that impinge upon HIF-2 including in rare cases, mutations of HIF-2 itself. So I’m cautiously optimistic HIF-2 inhibitors will be useful for paragangliomas. Outside of these tumors I am not sure yet where else these drugs will find a role. There has been some suggestion HIF-2 is important in glioblastoma cells, but I think the jury is still out here.
Could your work be relevant to neuroendocrine tumorigenesis? Could it translate into new potential therapeutic strategies to treat these rare tumors?
Some neuroendocrine tumors have mutations in genes that directly or indirectly alter oxygen sensing, including mutations in VHL, HIF-2, SDH, or EGLN2. We are therefore hopeful that pharmacologically modulating HIF will be useful in such tumors. For technical reasons it was easier to first study the role of VHL and HIF in kidney cancers but we are actively looking at oxygen sensing in neuroendocrine cancers.
Do you think targeted biologicals or newer therapies will replace chemotherapy?
I think chemotherapy will continue to be important, at least in the near future, and will increasingly be used in combinations that also contain targeted agents. And it is important to remember that some chemotherapeutic agents are every bit as targeted, at least in terms of their biochemical specificity, as some of the newer targeted agents, and new biological insights might teach that they are were, in hindsight, targeting genetically encoded vulnerabilities in the cancers in which they work.
Can cancer cells be starved of oxygen, in a targeted treatment?
There are many ways to kill cancer cells but the challenge is always to find things that will kill cancer cells without killing normal cells. It is not obvious how one could starve tumors of oxygen without potentially harming patients. But now that we understand oxygen sensing better it might be possible to reimagine how you could alter oxygen delivery to tumors and/or their response to oxygen for therapeutic benefit.
How do you think this new finding will pave the way for new therapeutics in cancer? Is there anything that is already being worked on?
Our work helped highlight the importance of HIF, and particularly HIF-2, in kidney cancer. Drugs that inhibit the HIF-2-responsive growth factor VEGF are now approved for kidney cancer and drugs that inhibit HIF-2 itself look promising. But we know from decades of experience with diseases such as TB, AIDS, and cancer that using any one drug as monotherapy is a recipe for acquired resistance. So we need to be thinking about combinations of effective drugs if we are going to cure cancers such as kidney cancer.
We are currently looking for other therapeutic vulnerabilities that are created when cells inactivate the VHL gene. For example, we just reported that such cells have an increased requirement for CDK4 and 6 as well as an increased requirement for the EZH1 histone methyltransferase.
Dr. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer. So would the promotion of VHL be expected to inhibit cancer? Or is it more complicated?
Just knowing the functions of genes doesn’t always allow you to reliably predict whether they will promote or suppress tumor growth. Making things more complicated, there are many examples of genes that can promote tumor growth in one cell type and suppress tumor growth in another. As a result, I really rely on germline and somatic mutations to tell me which genes cancers care about and whether those genes are likely to promote or suppress tumor growth.
Knowledge that VHL was inactivated in most clear cell renal cell cancers, which is the most common form of kidney cancer, told us the VHL protein suppressed these cancers. We then showed that in this context deregulation of HIF-2, and not the more famous paralog HIF-1, was the problem. Drugs that inhibit the HIF-2-responsive growth factor VEGF are now mainstays of kidney cancer treatment and HIF-2 inhibitors look promising.
In most other cell types we presume VHL loss either does not promote tumor growth or, paradoxically, might constrain tumor growth. This is something we are actively pursuing. Along these lines, I don’t know what solid tumors really rely on HIF-1, although can make some guesses.
How have the people you’ve worked with made you a better researcher?
It is really difficult, if not impossible, to be a good researcher if you are not surrounded by good people. Over my career I benefited from terrific mentorship from David Livingston, MD, from tremendous collaborators and colleagues. Moreover, the experiments that led to my receiving the Nobel Prize were done by a series of outstanding postdoctoral fellows and students in my laboratory. I couldn’t have done any of this without them. If you want to know where good science is being done, follow the best young people.