Thomas A. Gardner, M.D.
Professor of Urology
Professor of Microbiology & Immunology
Description and summary of research focus of the laboratory
Dr. Gardner's laboratory investigates novel therapeutics and delivery techniques for urologic cancers including prostate, kidney, bladder and testis. One main focus of the laboratory is to investigate the use tumor- or tissue-specific promoters to provide transcriptional regulation of a therapeutic gene. One example of this approach is the osteocalcin promoter utility in both prostate and osteosarcoma. We have demonstrated in vitro experiments and in vivo pre-clinical models that the osteocalcin promoter can transcriptionally regulate the ultimate production of the herpes simplex virus thymidine kinase when delivered by a recombinant replication-deficient adenovirus. The osteocalcin promoter is active in osteoblastic tissues and is active in both of the osteoblastic tumors above. We have utilized this approach in a phase I clinical trial in men with metastatic prostate cancer and found the approach to be safe. Additionally tissue samples from these patients before, during and after this treatment revealed biological efficacy of this approach. Since the hsv-TK/prodrug suicide gene therapy used in this first trial is limited to killing dividing cells, we have recently finished the pre-clinical studies on an osteocalcin-replication restrictive adenovirus. The rationale of this virus places the production of the critical initial protein for adenoviral replication, E1a, under the transcriptional control of the osteocalcin promoter. This allows for osteocalcin promoter restricted adenoviral replication in cells capable of activating the osteocalcin promoter (i.e. prostate cancer and osteosarcoma). This approach is extremely powerful if it can be delivered to the cell. We have expanded our investigations to other urologic tumors such as renal cell carcinoma and testis cancer using similar approaches. Delivery of the adenovirus to the target tumor cell remains a major obstacle for the success of cancer gene therapy. Many groups are investigating methods to improve delivery. Dr. Gardner's laboratory is developing several methodologies to address the problem of delivery. We are combining regional delivery with transductional targeting of the adenovirus, which allows for concentrating the therapeutic oncolytic adenovirus to the target tissue. The transductional targeting is accomplished by coating the adenovirus with bi-specific antibodies capable of altering the general cell tropism to a tumor-specific tropism. The antibodies used have been chosen for their specificity and prior use in the clinic. The regional delivery techniques will lend themselves well to endovascular implementation in patients. Therefore the rapid translation of this approach from the bench to the clinic is possible.
- Gardner TA, Wada Y, Shirakawa T, Ko S-C, Kao C, Kim SJ, Yang L, Chung LWK. Osteocalcin promoter restricted adenoviral replication as a potential treatment of prostate cancer metastasis. Presented at the 8th International Conference on Gene Therapy of Cancer, San Diego, CA, December 1999. 1999 Vical Best Abstract Award
- Gardner, T.A., E.A. Bissonette, G.R. Petroni, R. McClain, M.H. Sokoloff, and D. Theodorescu.. Surgical and postoperative factors affecting length of hospital stay after radical prostatectomy. Cancer 89:424-30, 2000
- Koeneman, K.S., C. Kao, S.C. Ko, L. Yang, Y. Wada, D.F. Kallmes, J.Y. Gillenwater, H.E. Zhau, L.W. Chung, and T.A. Gardner. Osteocalcin-directed therapy for prostate-cancer bone metastasis. World J Urol 18:102-10, 2000.
- Shirakawa T, Gotoh, A, Gardner TA, Kao C, Zhang Z-J, Matsubara S, Wada Y, Hinata N, Fujisawa M, Hanioka K, Matsuo M, Kamidono S. P53 primary cultures of human prostate and an experimental rat model. J Gene Medicine Preprint 2(6):426-432, 2000.
- Gardner TA, Ko S-C, Yang L, Cadwell JS, Chung LWK, Kao C. Serum-free recombinant adenoviral production using a hollow fiber capillary system. Biotechniques 30:422-427, 2001.
- B.A., 1986, George Washington University, Washington, D.C.
- M.D., 1990, George Washington University Medical Center, Washington, D.C.
- Postdoctoral, 1996-1998, Urologic Oncology Research Fellowship, University of Virginia Health Sciences Center, Charlottesville, VA