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	Thomas O'Brien, PhD Professor Room 129 610-645-3507 610-645-2205 (fax) OBrienT@mlhs.org Professor Department of Dermatology and Cutaneous Biology Thomas Jefferson University

Thomas O'Brien, PhD

Research Summary

In the past few years, my colleagues and I have developed and characterized a transgenic mouse model (the K6/ODC mouse) in which susceptibility to skin cancer development is tightly (and reversibly) liked to transgene expression: when ornithine decarboxylase (ODC) activity is elevated, susceptibility to carcinogen-induced tumor development is high, whereas when ODC overexpression is prevented, susceptibility is low. There are several projects currently ongoing in the laboratory whose goals are to understand the basis for this ODC-mediated susceptibility to cancer. In our mouse genetics project, we are combining the K6/ODC transgenic model with a standard inbred strain approach to identify by likage analysis genetic loci that modify the strong enhancing effect of ornithine decarboxylase (ODC) overexpression on skin cancer susceptibility. Two kinds of modifier loci are being mapped: loci that modify the total tumor multiplicity and loci that modify the predisposition to carcinoma development. We have so far mapped at least 3 loci that modify tumor multiplicity (on chromosomes 6, 17, and X), the strongest of which (LOD scores = 6 or greater) are tumor resistance alleles in the BALB/cJ and C3H/HeJ strains. We have also mapped a carcinoma predisposing locus to chromosome 2. The eventual goal is to identify the genes at these loci by candidate gene or positional cloning approaches. The availability of the complete sequence of the mouse genome will greatly facilitate our ability to identify these important modifier genes.

In our human functional genomics project, we have recently demonstrated a significant functional difference between the two known human ODC alleles, due to the presence of a single nucleotide polymorphism (SNP) in a critical regulatory region of the gene. We have determined the allele frequencies in a large number of North American Caucasians and are currently evaluating the association of a putative ODC risk allele with cancer susceptibility in several case control studies. Preliminary results indicate a significant association of the ODC risk allele with prostate cancer, especially in smokers. This is an example of a gene-environment interaction affecting cancer risk. Our working hypothesis is that following environmental exposures, individuals with a particular ODC genotype exhibit increased Odc expression, leading to increased risk for tumor development.

Our translational research project grew out of the observation in the K6/ODC transgenic mouse model that malignant squamous cell carcinomas (SCC) induced by carcinogen exposure are remarkably sensitive to anti-polyamine therapy (i.e., inhibitors of ODC). Polyamines are a class of small molecular weight amines, whose synthesis by cells and tissues is controlled by ODC. In many cases, we were able to completely cure mice with large (> 1000 mm³) SCCs by systemic administration of an ODC inhibitor. We are currently evaluating a combination therapy involving two drugs, one that inhibits ODC and another that inhibits polyamine uptake from the microenvironment by the tumor. The eventual goal is to evaluate this novel therapeutic approach in human cancer patients, either as first line therapy or in an adjuvant setting. Because anti-polyamine therapy is quite non-toxic, even a response rate equivalent to standard therapy would be meaningful because of the substantial side effects of current therapies.

Recent publications:

1. Guo, Y., Cleveland, JL, and O'Brien, T.G. 2005. Haploinsufficiency for ODC modifies mouse skin tumor susceptibility. Cancer Res. 65: 1146-49.

2. O'Brien TG, Guo Y, Visvanathan K, Sciulli J, McLaine M, Helzlsouer KJ, Watkins-Bruner D. 2004. Differences in ornithine decarboxylase and androgen receptor allele frequencies among ethnic groups. Mol. Carcinog. 41: 120-123.

3. Visvanathan, K., Helzlsouer, KJ, Boorman, DW, Strockland, PT, Hoffman, SC, Comstock, GW, O'Brien, TG and Guo, Y. 2004. Association Among an Ornithine Decarboxylase Polymorphism, Andriogen Receptor Gene (CAG) Repeat Length and Prostate Cancer Risk. J. Urology 171:652-655.

4. Martinez, ME, O'Brien, TG, Fultz, KE, Babbar, N, Yerushaimi, II, QN, Guo, Y, Boorman, D, Einspahr, J, Alberts, DS, and Gerner, EW. 2003. Pronounced reduction in adenoma recurrence associated with aspirin use and a polymorphism in the ornithine decarboxylase gene. Proc. Natl. Acad. Sci. USA 100:7859-64.

5. Megosh, L., Hu, J., George, K., and O'Brien, T.G. 2002. Genetic Control of Polyamine-dependent Skin Tumorigenesis. Genomics 79: 505-512.

6. Coleman, C.S., Pegg, A.E., Megosh, L.C., Guo, Y., Sawicki, J.A. and O'Brien, T.G. 2002. Targeted expression of spermidine/spermine N1-acetyltransferase increases susceptibility to chemically-induced skin carcinogenesis. Carcinogenesis 23: 359-364.

7. Boorman, D.R., Guo, Y., Visvanathan, K., Helzlsouer, K., O'Brien, T.G. 2002. An automated fragment analysis method for determining androgen receptor CAG repeat length. BioTechniques July, 2002.

8. Ahmad, N., Gilliam, A.C., Katiyar, S.K., O'Brien, T.G, and Mukhtar, H. 2001. A definitive role of ornithine decarboxylase in photo-carcinogenesis. Am J Pathol 159:885-892.

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