BBS Faculty Member - William Kaelin

William Kaelin

Sidney Farber Professor of Medicine

Dana Farber Cancer Institute
Mayer Building, Room 457
450 Brookline Avenue
Boston, MA 02116
Tel: 617-632-3975
Fax: 617-632-4760
Email: william_kaelin@dfci.harvard.edu



Dr. Kaelin’s research seeks to understand how, mechanistically, mutations affecting specific genes cause cancer, with a particular focus on particular tumor suppressor genes. His laboratory is currently focused on studies of the VHL and RB tumor suppressor proteins in addition to oncogenic forms of IDH1 and IDH2. His long-term goal is to lay the foundation for new anticancer therapies based on the biochemical functions of such proteins. His work on the VHL protein helped to motivate the eventual successful clinical testing of VEGF inhibitors for the treatment of kidney cancer and the recent testing of HIF2 inhibitors for this disease. Moreover, this line of investigation led to new insights into how cells sense and respond to changes in oxygen, and thus has implications for diseases beyond cancer, such as anemia, myocardial infarction, and stroke. This work was recognized with the 2019 Nobel Prize in Physiology or Medicine. His group also showed that leukemic transformation by mutant IDH was reversible, setting the stage for the development and approval of mutant IDH inhibitors, and discovered how thalidomide-like drugs kill myeloma cells by degrading two otherwise undruggable transcription factors. He is currently trying to exploit this later paradigm to target other undruggable oncoproteins, such as K-Ras and c-Myc. Finally, Dr. Kaelin has a longstanding interest in exploiting synthetic lethal relationships in cancer for therapeutic benefit and is using modern genetic and pharmacologic approaches to identify proteins that, when inactivated, will selectively kill cancers with VHL, RB, or IDH mutations.



Last Update: 8/10/2020



Publications

For a complete listing of publications click here.

 


 

Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J.M., Lane, W.S., and Kaelin, W.G., Jr. (2001). HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464-468.

Losman, J.A., Looper, R.E., Koivunen, P., Lee, S., Schneider, R.K., McMahon, C., Cowley, G.S., Root, D.E., Ebert, B.L., and Kaelin, W.G., Jr. (2013). (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621-1625.

Lu, G., Middleton, R.E., Sun, H., Naniong, M., Ott, C.J., Mitsiades, C.S., Wong, K.K., Bradner, J.E., and Kaelin, W.G., Jr. (2014). The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305-309.

McBrayer, S.K., Mayers, J.R., DiNatale, G.J., Shi, D.D., Khanal, J., Chakraborty, A.A., Sarosiek, K.A., Briggs, K.J., Robbins, A.K., Sewastianik, T., et al. (2018). Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175, 101-116 e125.



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