My research objectives are aimed at understanding the underlying genetics and biochemical mechanisms that govern the response of cells and tissues to both radiation and drug sensitivity in the context of cancer therapy. I am particularly interested in the intrinsic sensitivity to cancer therapy agents. In understanding intrinsic differences amongst individuals it is thought that we may begin tailoring cancer therapy to the individual and not to the population overall. This includes establishing biomarkers that will predict the efficacy of a given therapy based upon the underlying gene or protein expression patterns of the tumor as well as the normal tissue of an individual. These studies are by and large based upon large-scale gene expression analysis. My laboratory is also interested in using the same technologies to describe the normal tissue response to radiation of a very unique nature, that being, the types of radiation only seen in the space environment. These high molecular weight, highly energetic charged particles have unique biological properties that are of interest to the manned space program. Of particular interest is the enhanced carcinogenic potential, which my laboratory is now studying for leukemogenesis, and lung cancer. In the context of cancer etiology through our examination of intrinsic radiosensitivity we have built human models where we have identified alterations in genes associated with DNA repair. These genes are also linked to patient response to therapy in that patients displayed severe adverse reactions to their therapy. We intend to determine if these genetic alterations are causally linked to cancer and/or adverse therapeutic response through genomic instability via compromised DNA repair or other biochemical pathways that we have not yet identified. My laboratory cloned the mouse and human cDNAs of the gene whose subsequent protein is now known as GST Omega 1. The activity of this protein was first associated with the abrogation of apoptosis. Subsequently it has been associated with anthracycline resistance through the inhibition of differentiation, and it is also one of the enzymes that leads to arsenic biotransformation. We are examining the role of GSTO in the combination of arsenic and arsenic plus radiation as arsenic compounds are found to be very effective against some leukemias but have not yet been used in combination therapy or against other cancers. GSTO may also serve as a biomarker for the efficacy of chemotherapy agents like the anthracyclines as well as arsenical compounds.
RESEARCH INTERESTS
Carcinogenesis associated with HZE particle exposure
Intrinsic radiosensitivity
molecular markers of radioresponse
Modulation of drug and radiation response by GSTO expression
Radiotherapy research: SBRT and other
RECENT PUBLICATIONS
Giri, U., Terry, N. H. A., Story, M.D., "Elimination of the differential chemoresistance between the murine B-cell lymphoma LY-ar and LY-as cell lines after arsenic (As2O3) exposure via the overexpression of GSTO1 (p28). ." Cancer Chemother Pharmacol, 55:511-521, 2005
Nishikawa, T., Munshi, A., Story, M.D., Ismail, S., Stevens, C., Chada, S., and Meyn, R.E., "Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small cell lung cancer cells." Oncogene, 23:7125-7131, 2004
Buchholz, T. A., Weil, M. M., Ashorn, C. L., Strom, E. A., Sigurdson, A., Bondy, M., Chakraborty, R., Cox, J. D., McNeese, M. D., and Story, M.D., "A Ser49Cys variant in the ataxia telangiectasia, mutated (ATM) gene that is more common in breast cancer patients compared to population controls." Cancer, 100:1345-1351, 2004
Ismail, S.M., Puppi, M., Prithivirasingh, S., Raju, U., Meyn, R. E., Buchholz, T. A., Story, M.D., Brock, W.A., Milas, M., Thames, H. D., and Stevens, C.W., "Predicting radiosensitivity using DNA end-binding complex analysis." Clin. Cancer Res., 10:1226-1234, 2004
Zhang, X, Succi, J, Feng, Z, Prithivirajsingh, S, Story, M.D. and Legerski, R.J., "Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response." Molec. Cell Biol, 24:9207-9220, 2004
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