The Paul Marks Prize for Cancer Research was created by the Boards of Memorial Sloan Kettering Cancer Center to honor the late Paul Marks, who served as President and CEO of MSK for almost 20 years, beginning in 1980. Awarded every other year since 2001, the prize recognizes a new generation of leaders in cancer research who are making significant contributions to the understanding of cancer or are improving the treatment of the disease through basic or clinical research.
The winners of the 2021 prize were announced in November 2021. They will present their work at a series of online lectures hosted by MSK in March 2022.
Here, one of the winners, Sun Hur, discusses her career and current research. Dr. Hur is the Oscar M. Schloss Professor at Harvard Medical School and Boston Children’s Hospital and an investigator in the Howard Hughes Medical Institute.
How did you get interested in cancer research?
I did my postdoctoral training in X-ray crystallography, focusing on the molecular mechanisms of important biological processes. I then established my own lab, where I study how the immune system recognizes viral RNA and how this triggers the innate immune response. The innate immune response is the body’s first line of defense against pathogens, including viruses. But when it goes wrong and the immune system identifies part of the body as foreign, it can lead to autoimmunity.
After my early discoveries, several people working in the field of cancer biology figured out that radiation therapy and certain chemotherapy drugs activate some of the same pathways in the same receptors that my lab had been studying. When that happens, it causes inflammation in tumors, which can stimulate the immune system to help fight the cancer. That led my lab to start looking at cancer as well.
How do you go about studying the innate immune response?
An effective immune response against viral infection depends on a set of receptors that detect viral RNA. One of these receptors is MDA5, which recognizes viral RNAs on the basis of their structure, length, and modifications. With my background in structural biology and chemistry, I’ve been able to look at these immune receptors and modulators at the atomic level. Using crystallography, we determined the structure of MDA5 in complex with viral RNA mimetic and showed how the formation of filaments enables accurate detection of foreign RNA and activation of antiviral signaling pathways. Additional research has focused on other components of this signaling pathway, including another receptor called RIG-I.
Along the way, by using biochemical and cell biology approaches, we have discovered and defined key molecular interactions and their structural architectures involved in this intracellular signaling pathway and how they ultimately lead to the accurate discrimination between self and non-self.
What is the potential impact of this research for people with cancer?
Research in immuno-oncology has suggested that if you can precisely activate the immune response pathway in a very controlled manner, it could make cancer therapy more effective. Obviously, chemotherapy and radiation therapy can be very toxic and cause a lot of cell damage. If we can elicit an innate immune response without the toxicity of these other treatments, it could really benefit patients.
We are currently investigating ways to modulate this pathway — to turn it on in the context of cancer, and to turn it off in the context of inflammatory disease. We hope to develop small molecules that could be used as drugs that work in a precise manner. This would be a completely new kind of immunotherapy.
Beyond cancer, are there other diseases for which your research has potential applications?
This pathway is also implicated in lupus, an autoimmune disease. Lupus has a complex genetic background and can affect a number of different systems in the body. We’re trying to find biomarkers that we could use to identify patients with lupus whose inflammation is associated with the activation of this specific pathway. That way, if we develop a drug to block the pathway, we can use the biomarker to identify who is most likely to benefit from it.
Right now, we are studying these mechanisms on a biochemical basis, but we want to move this research into cell cultures and later mouse models so that we can eventually study it in clinical trials for patients.