William G. Kaelin, Jr. MD won the 2019 Nobel Prize in medicine. His research findings at Dana-Farber are game-changing: a rare disorder called von Hippel Lindau syndrome, triggered when one tumor-suppressor gene called VHL mutates, makes patients more likely to develop cancer. His exploration contributed to the finding that the VHL suppressor gene mutation causes kidney tumors to produce a protein called VEGF—fueling cancerous tumors with the vital extra blood supply needed to mature. This breakthrough led to the successful clinical testing of VEGF inhibitors that cut off this supply, and the creation of more than a dozen new therapy options. Sunitinib (Sutent) was the first anti-VEGF drug. Since then, many lives have been saved.
Receiving his MD from Duke University, Kaelin later became chief resident in internal medicine at Johns Hopkins Hospital. Thereafter, he pursued research of tumor suppressor proteins at Dana-Farber Cancer Institute in the laboratory of Dr. David Livingston, ultimately becoming an independent investigator and Professor of Medicine at Harvard Medical School. Today, he holds this same title at Harvard as well as Senior Physician of Medicine, Brigham and Women’s Hospital. At Dana-Farber/Harvard Cancer Center, he participates in the Cancer Cell Biology program and co-leads the Kidney Cancer Program.
Kaelin is the 2016 recipient of the Albert Lasker Award for Basic Medical Research. He also won the 2016 ASCO Science of Oncology Award and 2016 AACR Princess Takamatsu Award. In 2019, he became a Nobel Laureate in Physiology or Medicine with Peter J. Ratcliff and Gregg L. Semenza.
Dana-Farber Cancer Institute Research
Today, Kaelin is at the Dana-Farber Cancer Institute where his research focuses on the study of tumor suppressor genes and the normal functions of the proteins they encode. Ultimately, his research is laying the foundation for new protein tumor suppressor-based anticancer therapies. For example, their lab and team envision the development of drugs that mimic the behavior of a particular protein (tumor suppressor); or therapies that selectively, and with precision, kill the cells where tumor suppressor proteins have been inactivated—thus sparing the healthy cells.
Their current concentration today is the von Hippel-Lindau tumor suppressor protein (pVHL), the retinoblastoma tumor suppressor protein (pRB), and the p53-like protein called p73. These are important—for example, pVHL inactivation is common in several cancers, including clear cell renal carcinoma. Their laboratory established that upon available oxygen, pVHL targets for destruction another protein called hypoxia-inducible factor (HIF). He and team found that cells lacking pVHL (e.g. starved for oxygen) accumulate HIF, which activate a number of genes that help adjustment to hypoxia.
Kaelin and team demonstrated that the downregulation of HIF is necessary and adequate to suppress the growth of renal carcinomas in experimental models. These findings contributed to clinical trials of investigational agents that inhibit HIF-responsive growth factors, such as vascular endothelial growth factor (VEGF).
A Life Saved
Kaelin’s work has led to the development of treatments such as sunitinib (Sutent) first approved by the FDA in 2006. This drug inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs)—including VEGF and platelet-derived growth factors (PDGF-Rs), which play a role in both tumor angiogenesis and tumor cell proliferation. The simultaneous inhibition of these targets reduces tumor vascularization and triggers cancer cell apoptosis—resulting in tumor shrinkage.
Shaun Tierney, a Massachusetts resident was diagnosed with stage IV kidney cancer. The engineer and father was told by his physician he wouldn’t live much longer. But after a second opinion, he began working with a protégé of William G. Kaelin, Jr. named Toni Choueiri, MD, who directs the Lank Center for Genitourinary Oncology. The treatment plan—including Sutent—ultimately saved Tierney’s life. In fact, Tierney credits Kaelin’s research from over a decade ago for contributing to his ability to have more time to spend with his supporting wife while watching his three adult children raise their families—including six grandchildren.
This next chapter of life for Shaun Tierney was made possible by a lot of hard working, dedicated and committed scientists, researchers and health professionals who live themselves to see others live. William G. Kaelin, Jr. understands the power of life for the individual in that the human story is only richer and deeper if we can keep people alive to share more of the present moment.