Department of Surgery, Division of Surgical Oncology
- gene expression profiling of human tumors
- study of novel therapeutic targets
- development of novel therapies
- evaluation of novel therapeutics
- pancreatic and colorectal cancer
The overall goal of the lab is to identify and study novel therapeutic targets for the treatment of colorectal and pancreatic cancer. Pancreatic cancer in particular continues to be a lethal disease with few therapeutic options. Our research therefore centers on target identification through gene expression profiling of human tumors -> validation -> drug discovery and finally clinical trials.
Identification of therapeutic targets
Efforts to identify parallel aberrant signaling pathways that are critical for tumor progression and metastasis are critical for cancer treatment. It is clear that cancers rarely respond to the same therapies. Genomic analyses of actual human tumors may be helpful to identify more selective targets and biomarkers for the identification of pathways or genes that tumors may be “addicted” to. We have used gene expression profiling to identify signatures for pancreatic and colorectal cancer. In doing this we have identified several candidate genes important in metastatic and primary pancreatic cancer, and colorectal cancer.
Mechanisms of tumorigenesis and metastasis
A major focus of the lab is to study novel candidate genes and their roles in tumorigenesis and metastasis. One facet of these studies involves the dissection of the complex signaling mechanisms that relate to these candidate genes and their role in tumor growth. A long-term goal of these studies is to use this information for the development of anti-tumor drugs as novel approaches for cancer treatment.
Evaluation of novel therapeutics
One major challenge in selecting targets for drug development, and patients for drug therapies, is the limited predictive value of traditional preclinical models, cell line derived xenografts. Less than 5% of promising therapies reach the clinic. In order to better address and capture the inherent heterogeneity found in tumors and patients, we have established a Patient Derived Tumorgraft (PDT) Program where we have engraft actual human tumors into mice. We have also recapitulated and recharacterized KRAS-driven mouse models of pancreatic and colorectal cancer which we use for the study of our candidate genes and for novel therapeutics. With the increasing recognition that PDT and GEMMs are more accurate predictors of drug response and better models for biomarker and therapeutic discovery, these models are an exciting first step for the translation of our laboratory studies into clinical trials. We have a number of ongoing collaborations for the development of novel anti-tumor therapies and delivery techniques.
Click above for PubMed publications.
- Stratford, J.K., Bentrem, D.J. , Anderson, J.M., Volmar, K.A., Marron, J.S., Fan, C., Routh, E.D., Caskey, L.S., Samuel, J.C., Der, C.J., Thorne, L.B., Calvo, B.F., Kim, H.J., Talamonti, M.S., Iacobuzio-Donahue, C.A., Hollingsworth, M.A., Perou, C.M., and Yeh, J.J. (2010) A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma. PLoS Medicine, in press.
- Goicoechea, S.M., Bednarski, B., Stack, C., Cowan, D.W., Volmar, K., Thorne, L., Cukierman, E., Rustgi, A.K., Brentnall, T., Hwang, R.F., McCulloch, C.A.G., Yeh, J.J., Bentrem, D.J., Hochwald, S., Hingorani, S.R., Kim, H.J., and Otey, C.A. (2010) Isoform-specific upregulation of palladin in human and murine pancreas tumors. PLoS ONE, 5(4):e10347.
- Kim, W.Y., Perera, S., Zhou, B., Carretero, J., Yeh, J.J., Heathcote, S.A., Jackson, A.L., Nikolinakos, P., Ospina, B., Naumov, G., Brandstetter, K.A., Weigman, V.J., Zaghlul, S., Hayes, D.N., Padera, R.F., Heymach, J.V., Kung, A., Sharpless, N.E., Kaelin, W,G,, and Wong, K.K. (2009) HIF2a cooperates with RAS to promote lung tumorigenesis in mice. Journal of Clinical Investigation, 119(8): 2160-79.
- Yeh, J.J. (2009) A prognostic signature in pancreatic cancer: are we close? Future Oncology, 5(3): 313-21.
- Yeh, J.J., Routh, E.D., Rubinas, T., Martin, T.D., Peacock, J., Wu, D., Sandler, R., Kim, H.J., Keku, T., and Der, C.J. (2009) ERK1/2 activation as a biomarker for MEK1/2 inhibitor therapy in colorectal cancer. Molecular Cancer Therapeutics, 8(4): 834-43.
- Yeh, J.J., and Der, C.J. (2007) Targeting signal transduction in pancreatic cancer treatment. Expert Opinion on Therapeutic Targets, 11(15): 673-94.