Research Groups

Cancer Genomics

Research Interests and Description

Group Members
Juliano Domiraci Paccez, Postdoc
Rodrigo Esaki Tamura, Postdoc
Kristal Duncan, Research Technician

Research Interests

Regulation of gene expression by transcription factors, role of receptor tyrosine kinases in cancer malignancies, aberrant gene expression in carcinogenesis, alterations in signal transduction pathways and gene translocations.

Description of Research

The overall goals of the Cancer Genomics group are to utilize genomics and proteomics tools and signal transduction resources to accelerate comparative analysis of aberrant gene expression in carcinogenesis and to study alterations in signal transduction pathways during development of cancers.
Transcription factors, Cell Survival and Apoptosis
We recently identified the two members of the GADD45 family as key players in apoptosis induction of cancer cells and inhibition of tumor formation. We demonstrated that GADD45α and GADD45γ repression plays an unambiguous and universal role in the ability of tumors to escape programmed cell death. Analysis of in vivo interacting proteins using a mass spectrometry approach identified the cdk11 p58 and a DCND1 (defective in cullin neddylation 1) as partners of the GADD45 family members.
Transcription factors, translocations and degradation
A number of transcription factors are overactive in most human cancer cells, making them good targets for the development of anticancer drugs. A major recent breakthrough was the identification of recurrent fusions between an androgen regulated gene (TMPRSS2) and one of two Ets transcription factors (ERG and ETV1) in a series of primary prostate cancers. Our studies also focus on determining the biological relevance of ERG translocations in prostate cancer. Current efforts are also focused toward understanding how transcription factors are regulated and more importantly, degraded.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and MDA-7/IL-24
A third major goal of our group is to elucidate the molecular mechanisms of cancer apoptosis induction by structurally different Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Our current analysis of NSAIDs treatment of cancer cells demonstrated that NSAIDs mediate apoptosis via induction of the pro-apoptotic cytokine interleukin 24 (IL-24). Our efforts focus on dissecting the molecular mechanisms of apoptosis induction by NSAIDs and on chemically modified versions of NSAIDs as novel entry points that are more specific against cancer and with less adverse reactions. This approach may allow the rational design and treatment with drugs with distinct target specificities that could act synergistically and thus more effectively against cancer.
The Role of tyrosine kinase receptors in Cancer Development
Our group also focused on identification of potential therapeutic targets that are upregulated in cancer with particular emphasis on cell surface receptors. We identified several tyrosine kinase receptors whose expression was specifically increased in cancer when compared to control or other subtypes. AXL is most consistently upregulated tyrosine kinase receptor. Our hypothesis is that targeting the AXL tyrosine kinase will inhibit cancer growth and thus lead to a novel therapeutic entry point for cancer.

Recent Publications

Bruns, I., Czibere, A., Fischer, J.C., Roels, F., Cadeddu, R.P., Buest, S., Bruennert, D., Huenerlituerkoglu, N.H., Stoecklein, A.N., Singh, R., Zerbini, L.F., Jager, M., Kobbe, G., Gattermann, N., Kronenwett, R., Brors, B., Haas, R. 2009. The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence. Leukemia. In press

Cho, J.Y., Lee, M., Park, E.S., Ahn, J.M., Cho, J.H., Lee, S.J., Kim, B.J., Heo, S.H., Park, H.J., Zerbini, L.F., Hwang, D., Libermann, T.A. 2009. Proteomic analysis of a PDEF Ets Transcription Factor-interacting Protein Complex. Journal Proteome Research. In press

Konstantinopoulos, P.A., Fountzilas, H., Zerbini, L.F., Pillay, K., Libermann, T.A., Cannistra, S.A., Spentzos, D. 2008. Carboplatin-induced gene expression changes in vitro are associated with survival in patients with epithelial ovarian cancer. BMC Genomics 1, 59

Dusek, J.A., Out, H.H., Wohlhueter, A.L., Bhasin, M., Zerbini, L.F., Libermann, T.A., Benson, H. 2008. Genomic Counter-Stress Changes Induced by a Mind Body Practice. Plos One 3: e2576

Ijiri, K., Zerbini, L.F., Peng, H., Out, H.H., Tsuchimochi, K., Otero, M., Dragomir, C., Walsh, N., Bierbaum, B.E., Mattingly, D., Flandern, G., Komiya, S., Aigner, T., Libermann, T.A., Goldring, M.B. 2008. A Differential expression of GADD45β in normal and osteoarthritic cartilage: Potential role in homeostasis of articular chondrocytes. Arthritis and Rheumatisms. 58: 2075-2087