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	Janet Sawicki, PhD Professor Rm. 134 610-645-3123 610-645-2205 (Fax) Sawickij@mlhs.org Associate Professor Department of Dermatology and Cutaneous Biology Thomas Jefferson University

Janet Sawicki, PhD

Research Summary

Approximately 30,000 men die from prostate cancer and 14,000 women die from ovarian cancer each year in the U.S. Despite technical advances, the main treatments used today to treat cancer -- surgery, radiation therapy, and chemotherapy -- reduce tumor burden but are not curative in about half of cancer patients, most of whom die because they have metastatic disease. Successful treatment of metastatic disease is a great challenge because tumors develop throughout the body, requiring systemic administration of therapy to the patient. Surgical procedures are impractical, and effective doses of radiation and chemotherapy therapy often damage or are toxic to normal cells.

Systemic delivery of targeted gene therapy holds great promise for improving the treatment of metastatic cancers, including prostate and ovarian cancer. Targeted therapy can be accomplished by restricting the delivery of DNA to specific cells and/or restricting the expression of genes to certain cell populations. In our laboratory, we are developing a gene therapy strategy to deliver and effectively target expression of a so-called suicide gene encoding diphtheria toxin, DT-A, to prostate and ovarian tumor cells. This toxin is an especially potent inhibitor of protein synthesis, so its expression in tumor cells results in their death. We are exploring ways to modify both viral and non-viral vectors to deliver the DT-A gene specifically to tumor cells and to neovasculature associated with tumors. A new class of polymers, poly(b-amino esters), developed at MIT by our collaborator, Robert Langer, condense DNA into nanoparticles, and show promise as an effective new way to deliver DNA systemically to patients, while avoiding adverse toxicity and immunogenic responses associated with other vectors. We are also studying the utility of different genetic regulatory elements for targeting DT-A expression to prostate and ovarian tumor cells. We use transgenic mouse models for prostate and ovarian cancer, and imaging technologies (optical bioluminescence and microCAT) to test the efficacy of new therapeutic designs.

In related research, we are working to identify adult stem cells in the prostatic epithelium and fetal stem cells harbored by mothers after they have given birth. Identification of these cells will lay the groundwork for the development of cell therapy strategies for the treatment of cancer and other diseases in the future.

Selected Publications

Peng, W., Chen, J., Huang, Y.-H., and Sawicki, J.A. 2005. Tightly regulated suicide gene expression kills PSA- expressing prostate tumor cells. Gene Therapy, In press.
Bao Y, Peng W, Verbitsky A, Chen J, Wu L, Rauen KA, Sawicki JA. (2005). Human coxsackie adenovirus receptor (CAR) expression in transgenic mouse prostate tumors enhances adenoviral delivery of genes. Prostate, in press.
Anderson DG, Peng W, Akinc A, Hossain N, Kohn A, Padera R, Langer R, Sawicki JA. (2004). Polymer library approach to suicide gene therapy for cancer. Proc. Natl. Acad. Sci USA 101: 16028-16033.
Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, Lin JS, Sawicki JA, Cotsarelis G. (2004). Capturing and profiling adult hair follicle stem cells. Nature Biotechnol. 22: 411-417.
Sawicki, J.A. and Rothman, C.J. (2002). Evidence for stem cells in cultures of mouse prostate epithelial cells. Prostate 50: 46-53.
Peng, W., Verbitsky, A., Bao, Y., and Sawicki, J.A. (2002). Regulated expression of diphtheria toxin in prostate cancer cells. Molecular Ther. 6: 537-545.

Funding

NIH grant #CA90841. "Targeted Death of Prostatic Cancer Cells"
Sharpe Foundation. "Nanoparticle Delivery of a Therapeutic Gene for the Treatment of Prostate Cancer"

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