A. Thomas Look, M.D.
Professor of PediatricsDana-Farber Cancer Institute
A. Thomas Look, M.D., is a Professor of Pediatrics at Harvard Medical School and a member of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute, as well as a co-Leader of the Dana-Farber/Harvard Cancer Center’s Leukemia Program. He is the principal investigator on several NIH-funded grants, including an R35 Outstanding Investigator Award from NCI. Look received his M.D. degree and postgraduate training in Pediatrics from the University of Michigan and his fellowship training in Pediatric Oncology at St. Jude Children’s Research Hospital, where he advanced over twenty years to become Chair of the Experimental Oncology Department. Prior to his appointment at Harvard, he was a professor at the University of Tennessee College of Medicine. Over the past four decades, Look has published 348 peer-reviewed papers addressing the molecular basis of malignant transformation, aberrant proliferation and apoptosis in cancer cells and the application of molecular genetic findings to improve the treatment of malignancies of children and adults, particularly T-cell acute leukemia, neuroblastoma and myelodysplastic syndrome. He moved from St. Jude Children’s Research Hospital to Dana-Farber Cancer Institute in 1999 specifically to establish a research program in the zebrafish as a model of human cancer. Look has conducted genetic studies aimed at the identification of novel targets for cancer therapy, and he is now internationally recognized as a leader in this field. His laboratory has developed the first zebrafish transgenic models of T-cell acute lymphoblastic leukemia and childhood neuroblastoma, opening up the opportunity to apply the powerful genetic and chemical biology technology applicable to the zebrafish model to identify new molecular targets and small molecule drugs for therapy in these childhood cancers. His laboratory has also developed the first zebrafish models of myelodysplastic syndrome and clonal hematopoiesis due to loss of TET2, ASXL1 and DNMT3A, which he is using to identify drugs that selectively target mutant hematopoietic stem and progenitor cells, while sparing normal hematopoiesis. Recently, his group identified a class of small molecules called iHAPs, or improved heterocyclic activators of PP2A, that kill leukemia and solid tumor cells by allosterically assembling a specific heterotrimeric protein phosphatase 2A (PP2A) holoenzyme containing the B56ε regulatory subunit. These compounds stimulate PP2A-B56e phosphatase activity but do not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase, but is not toxic to normal dividing cell populations.