William G. Kaelin, Jr., MD, of the Dana-Farber Cancer Institute, Harvard Medical School, is being honored with the 2016 Science of Oncology Award and Lecture for providing invaluable insights into the biochemical functions of tumor suppressor proteins and their roles in cancer development. Dr. Kaelin has dedicated the better part of his career to understanding how mutations in tumor suppressor genes affect cancer onset and progression and to laying the foundation for the development of novel anticancer therapies based on this knowledge.
Dr. William G. Kaelin
Dr. Kaelin finds it especially gratifying that his peers have taken the time to acknowledge the quality of his work in the form of an award such as the one being presented to him by ASCO. “Most investigators know that you are only as good as the people you work with, especially your trainees,’’ he said in an interview with the ASCO Daily News. “I have had the privilege and good fortune of working with many incredibly talented young people who, collectively, made the discoveries being recognized by this award.’’
On a more personal note, he added: “I would also like to acknowledge my late wife, Dr. Carolyn Kaelin, who was my best friend and partner in life. She selflessly supported me throughout my career with grace.’’
Tumor Suppressor Proteins and Their Role in Cancer
Dr. Kaelin completed his training in internal medicine at Johns Hopkins Hospital and his clinical fellowship in medical oncology at Dana-Farber. He assumed the position of associate director of Basic Science at the Dana-Farber/Harvard Cancer Center in 2008. He currently directs a research laboratory that consists of 13 postdoctoral fellows and two medical students.
His research at Dana-Farber has focused on understanding the role of mutations in tumor suppressor genes in cancer development. His work on the retinoblastoma (RB), von Hippel-Lindau (VHL), and p53 tumor suppressors indicated that correcting a single genetic defect in genetically complex neoplasms can produce therapeutic effects in preclinical models.
“This has galvanized efforts to treat tumors lacking specific tumor suppressors by targeting proteins that are downstream (‘epistatic’) of those tumor suppressor proteins or by identifying unique vulnerabilities created upon loss of those tumor suppressor proteins (‘synthetic lethality’),’’ he explained.
Among his most notable accomplishments, Dr. Kaelin’s work has provided a conceptual foundation for the successful development of VEGF inhibitors for kidney cancer. “We discovered that the VHL tumor suppressor protein, which is defective in most kidney cancers, is a critical component of the circuit that couples changes in oxygen availability to the abundance of hypoxia-inducible mRNAs, such as the VEGF mRNA,’’ he said.
In the course of his work on the VHL protein, Dr. Kaelin’s team uncovered a previously unanticipated role for prolyl hydroxylases in signal transduction, which has set the stage for the development of prolyl hydroxylase inhibitors for diseases associated with impaired oxygen delivery, such as myocardial infarction and stroke.
Identifying New Cancer Targets
Dr. Kaelin’s group is presently focused on identifying new functions of the VHL tumor suppressor protein and new ways to treat cancer cells that lack this protein. They are also trying to understand how IDH1 and IDH2 mutations cause cancer and are working on developing strategies to treat IDH-mutated tumors. “Many potential targets in cancer, such as KRAS and c-Myc, would classically be viewed as ‘undruggable,’” Dr. Kaelin said. “We are trying to develop new approaches for destabilizing such proteins, building on our recent work on thalidomide-like drugs and the myeloma oncoproteins IKZF1 and IKZF3.”
In the long run, he hopes that his team and the broader scientific community will have contributed to substantial improvements in cancer treatment through the discovery of better targets and agents and by providing the knowledge needed for more intelligent clinical trials. He believes that these trials would need to involve appropriate predictive biomarkers and drug combinations.
Dr. Kaelin has authored or co-authored 120 peer-reviewed publications. In recognition of his dedication to science and cancer research, he is a Howard Hughes Medical Institute Investigator and was elected to the Institute of Medicine (now National Academy of Medicine) in 2007, the National Academy of Sciences in 2010, and the American Association for Cancer Research Academy in 2014. As the Science of Oncology Award recipient, he joins the list of top oncologists who have made exceptional contributions to the fundamental understanding of cancer.
During his lecture on June 5, he will provide a historical overview of his work on the VHL tumor suppressor protein and its role in oxygen sensing and cancer.
– Jasenka Piljac Žegarac, PhD