Roger Briesewitz, Ph.D.

Research Interests

Since the discovery of the first oncogenes more than two decades ago, the prospect of targeted therapy promised to make cancer drugs better tolerated, less toxic and potentially more efficacious. In recent years the first targeted therapies have entered the clinic and some of these new drugs have been veritable breakthroughs because they induce cell death (apoptosis) selectively in the cancer cell. Our research interest lies in understanding why certain targeted therapies can induce apoptosis in cancer cells. This may help to focus on the best targets in cancer drug discovery and may yield insights for new therapeutic approaches.Research Focus:

Among the most promising targeted therapeutics in cancer are tyrosine kinase inhibitors. Tyrosine kinases play an important role in proliferation and survival of cells so that it is not surprising that they have been implicated in oncogenesis. Mutations in tyrosine kinases can lead to the deregulation of the kinase activity which may contribute to oncogenesis. The tyrosine kinase abl is a prominent example of a kinase that is activated through mutation. In chronic myeloid leukemia (CML), a part of the abl gene is fused to a part of the bcr gene due to a translocation between chromosome 9 and 22. The resulting bcr-abl fusion has constitutively active kinase activity that gives rise to cancer. Recently, the abl kinase inhibitor Gleevec has entered the clinic for the treatment of CML and has shown extraordinary efficacy.

Gleevec is not specific for the abl kinase, instead, the drug also inhibits a number of other kinases like c-kit, PDGFRA and PDGFRB. C-kit is mutationally activated in gastro-intestinal stromal tumors (GIST) and Gleevec has become a breakthrough therapeutic in this cancer because the inhibition of mutated c-kit leads to apoptosis of GIST cells. Similarly, Gleevec has shown great efficacy in hypereosinophilic syndrome (HES), a form of myeloproliferative disease in which PDGFRA is mutationally activated.

Gleevec is not the only kinase inhibitor that has shown efficacy in cancer. For example, in 30% of AML patients the receptor tyrosine kinase Flt3 is mutationally activated. Flt3 inhibitors will induce apoptosis in AML cell lines that carry an activating Flt3 mutation and Flt3 inhibitors are showing promising results in ongoing clinical trials.

We are interested in understanding why cells undergo apoptosis if they lose the signal that is derived from the mutated kinase upon exposure to a kinase inhibitor. For our studies we are using cancer cell lines that express mutated kinases as well as appropriate kinase inhibitors. These valuable tools allow us to perform phosphoproteomics and gene expression experiments that elucidate the signaling pathways activated by mutated kinases. The obtained insights are validated by molecular and cell biological approaches as well as in mouse models.

By understanding signaling of mutated kinases we may gain insights for additional drug targets downstream of the mutated kinase. The crucial survival pathway activated by mutated kinases may also be activated by other oncoproteins, hence, any insights gained from the signaling pathways of mutated kinases may also apply to other oncoproteins in different types of cancer.

Selected Publications:

Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T, Liso A, Diverio D, Mancini M, Meloni G, Goa R, Martelli MF, Mecucci C, Croce CM, Falini B. (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucelophosmin.  Proc Natl Acad Sci USA 105(10):3945-3950.

Wang L, Wang J, Blaser BW, Duchemin AM, Kusewitt DF, Liu T, Caligiuri MA, Briesewitz R. (2007) Pharmacologic inhibition of CDK4/6: Mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. Blood 110(10):2075-2083.

Caliguiri MA, Briesewitz R, Yu J, Wang L, Wei M, Arnoczky KJ, Marburger TB, Wen J, Perrotti D, Bloomfield CD, Whitman SP. (2007).  Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood 110(3):1022-1024.

Sellmyer MA, Stankunas K, Briesewitz R, Crabtree GR, Wandless TJ (2007).  Engineering small molecule specificity in nearly identical cellular environments.  Bioorg Med Chem Lett 17(10):2703-2705.
 
Braun PD, Barglow KT, Lin YM, Akompong T, Briesewitz R, Ray GT, Haldar K, Wandless TJ. (2003) A bifunctional molecule that displays context-dependent cellular activity.  J Am Chem Soc125(25):7575-7580.

Griffin J, Leung J, Bruner R, Caligiuri MA, Briesewitz R. (2003). Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. PNAS 100:7830-7835.