Professor of Biological Chemistry and Molecular Pharmacology
Dana-Farber Cancer Institute
Smith Building, Room 970
44 Binney Street Boston, MA 02115
Lab Size: Greater than 10
Signaling Mechanisms and Cancer
Through the process of signal transduction, cells communicate what is happening on their surfaces to the regulatory machinery inside. This process is facilitated by a class of enzymes called kinases, which help activate specific genes in the long strands of DNA in a cell's nucleus. An overactive kinase can lead to an overactive gene and, ultimately, to cancer. Our laboratory is researching the role of these catalysts of cell growth and division and has discovered how several work. Our discoveries have become the basis of new drugs that target the actions of specific kinases. This class of drugs, called kinase inhibitors, offers extraordinary hope for the future of cancer care.
Research in the laboratory currently focuses on three areas. One is how particular kinases are involved in cancer. For instance, the kinase termed PI3K blocks the orderly process of cell death, called apoptosis. Thus, inhibiting PI3K should lead to tumor cell death. We are also exploring new ways to measure kinase activity in tumors. Every tumor is unique, with its own pattern of activated kinases. Because there are more than 600 different kinases in a given tumor, it is important to find which ones are activated so that we know which ones to inhibit. Finally, our laboratory is developing murine model systems to study kinases in tumors.
Once kinases have been pinpointed, our laboratory develops the techniques and technology that allow pharmaceutical companies to make new drugs that target them. We supply the company with the reagents necessary to test the effect of drugs on the action of tyrosine kinases. In addition, DFCI scientists have developed the means to make kinases for testing. This collaboration has led to the creation of several new drugs. In particular, the drug Gleevec has been approved by the FDA against chronic myeloid leukemia (CML). More recently we have been working with Novartis on PI3k inhibitors. PI3K inhbitors from Novartis and other companies are now entering Phase 2 trials
Jia S, Gao X, Lee SH, Maira SM, Wu X, Stack EC, Signoretti S, Loda M, Zhao JJ, Roberts TM (2013).
Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention Cancer Discov. 2013 3(1):44-51. PMCID: PMC3546223
Jia S*, Liu Z*, Zhang S*, Liu P, Lee S, Zhang J, Lee S, Zhang J, Signoretti S, Loda M, and Roberts TM, and Zhao JJ (2008). Essential roles of PI(3)K-p110b in cell growth, metabolism and tumorigenesis Nature 454:776-9. PMCID: PMC2750091.
Qi HH*, Sarkissian M*, Bhattacharjee A, Gordon B, Lan F, Huarte M, Yaghi NK, Lim H, Brizuela L, Roberts TM# and Shi Y# (2010). The mental retardation gene PHF8 mediates histone H3K9/H4K20 demethylation and regulates zebrafish craniofacial development. Nature 466:503-7. PMCID: PMC3072215.
Ilic N, Utermark T, Widlund HR, Roberts TM. (2011) PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc Natl Acad Sci U S A. Aug 29. Epub ahead of print
Tamara Utermark*, Trisha Rao*, Hailing Cheng, Qi Wang, Sang Hyun Lee, Charles Zhigang Wang, J. Dirk Iglehart, Thomas M. Roberts1, William J. Muller* and Jean J. Zhao* (2012) The p110 and p110 isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis Genes & Development 26(14):1573-86