Department of Pharmacology
Ph.D., Cell & Molecular Physiology
- Cancer pharmacology
- Genome-wide siRNA screens
- Identification of genes involved in survival, proliferation, and chemosensitivity of tumor cells
The goal of our research is to gain a mechanistic understanding of the core molecular components that specify tumorigenic phenotypes at the cancer cell autonomous level. To realize this goal, the laboratory employs genome wide siRNA screening to isolate gene products supporting the survival, proliferation and chemosensitivity of tumor cells. As an example, we have employed a synthetic lethal siRNA screen to identify chemosensitizer loci in non-small cell lung cancer cells. From this screen, we have identified a panel of genes with remarkable consequences on chemosensitivity that have either no previously recognized connection to tumorigenesis or strictly correlative connections. This work is the cornerstone of the research in the laboratory, and we are using a combination of cell biological and biochemical approaches to define mechanistic relationships between these targets and cancer cell biology.
The primary initial focus is on a subset of targets identified that are not expressed in normal lung tissue, and instead play roles in specialized processes such as gametogenesis or neuronal migration. We hypothesize that these targets are not simply silent byproducts of aberrant gene expression programs, but are required for tumorigenesis. Since many of these genes are dispensable for normal cell function, they provide a unique entry point for targeted therapeutic approaches. Preliminary mechanistic studies have demonstrated that depletion of a subset of these genes results in genotoxic stresses such as lagging chromosomes, multipolar spindles, or centrosomal duplication errors. While the action of the targets we have identified may or may not be direct on the mitosis, their requirement for proper mitosis invites the possibility that they may comprise a unique “cancer cell spindle” that promotes cell survival in the presence of genetic damage.
Traditionally we have used established tumor cell lines for screening and follow-up studies because of their suitability for genomic manipulations. Our long-term goal is translate our findings into a more clinically relevant context. Specifically, our ability to manipulate protein expression levels in primary tumor samples now gives us the opportunity to test our findings in established cell lines in primary tumor cell lines both in a cell culture setting as well as in xenograft systems.
Click above for PubMed publications.
- Whitehurst, A.W., Xie, Y., Purinto,n S.C., Cappell, K.M., Swanik, J.T., Larson, B., Girard, L., Schorge, J.O., and White, M.A. (2010) Tumor antigen acrosin binding protein normalizes mitotic spindle function to promote cancer cell proliferation. Cancer Res. 70(19): 7652-61. PMID: 20876808. Abstract
- Cappell, K.M., Larson, B., Sciaky, N., and Whitehurst, A.W. (2010) Symplekin specifies mitotic fidelity by supporting microtubule dynamics. .Mol Cell Biol. 30(21): 5135-44. PMID: 20823274. Abstract
- Cao, J., Xian X.,J.,Zhang, S., Whitehurst, A.W., White, M.A., (2009) Bayesian optimal discovery procedure for simultaneous significance testing. BMC Bioinformatics 10: 5. Abstract
- Xian, X.J., Whitehurst, A.W., and White, M.A. (2007) A statistical method for identifying high confidence hits in genome wide siRNA data sets. Nature Protocols Online. Article
- Whitehurst, A.W., Bodemann, B.O., Cardenas, J., Ferguson, D., Girard, L., Peyton, M., Minna, J.D., Michnoff, C., Hao, W., Roth, M.G., Xian, X.J., and White, M.A. (2007) Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 44: 815-819. Abstract
- Whitehurst, A.W., and White, M.A. (2005) Harnessing RNAi for Analyses of Ras Signaling and Transformation. Meth Enzymol 407: 259-68. Article