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Shafaat A. Rabbani, M.D. Professor, Department of Medicine, McGill University Associate Member, Departments of Physiology and Oncology, McGill University Health Centre Calcium Research Laboratory |
Research:
Breast Cancer; Prostate Cancer; Urokinase; Methylation; Parathyroid Hormone Related Peptide.
The main focus of research in my laboratory is to examine the molecular mechanisms involved in the progression of hormone dependent malignancies (breast and prostate cancer). Toward these objectives, we are examining the role of urokinase (uPA) in the process of tumor invasion, growth and metastasis. The change in the methylation status of uPA promoter is being evaluated as the epigenetic mechanism regulating uPA gene transcription in normal, early, and late stage breast and prostate cancer. Our group is developing novel diagnostic and therapeutic strategies to block uPA production and its interaction with cell surface uPAR to block tumor growth and metastasis. Using our well- established models of breast and prostate cancer which closely mimics the behavior of these cancers including their propensity to develop skeletal metastasis, we are examining the efficacy of small molecules, peptides, monoclonal antibodies, oligonucleotides, and gene therapy for further evaluation in patients with these common cancers. Additionally we are developing highly sensitive and reliable molecular approaches to determine the levels of uPA expression including methylation specific PCR which can predict the methylation status of uPA, invasive potential of tumor cells and response to therapy. These results will help design an effective therapeutic strategy to block uPA/uPAR interaction.
Since both breast and prostate cancer have a high propensity to develop skeletal metastases, we are evaluating the role of parathyroid hormone related peptide (PTHrP) in hypercalcemia of malignancy. Using our syngeneic and xenograft models of prostate and breast cancer we are examining the capacity of peptides and small molecules directed against prostate secretory proteins, integrins and intracellular signaling pathways to block the development and progression of skeletal metastases.
Selected Publications:
Rabbani, S.A., and Gladu, J. Urokinase receptor (uPAR) antibody can reduce tumor volume and detect the presence of occult tumor metastases in vivo. Cancer Res. 62: 2390-2397, 2002.
Guo, Y-J., Mazar, A.P., Lebrun, J-J., Rabbani, S.A. An anti-angiogenic urokinase derived peptide combined with tamoxifen (TAM) decreases tumor growth and metastasis in a syngeneic model of breast cancer. Cancer Res. 62(16):4678-4684, 2002.
Guo, Y-J., Pakneshan, P., Szyf, M., Rabbani, S.A. Regulation of DNA methylation in human breast cancer: effect on the urokinase-type plasminogen activator gene production and tumor invasion. J. Biological Chem. 277(44):41571-41579, 2002.
Pakneshan, P., Xing, R-H., Rabbani, S.A. Methylation status of uPA promoter as a molecular mechanism regulating prostate cancer invasion and growth in vitro and in vivo. FASEB J. 17(9):1081-1088, 2003.
Pakneshan, P., Têtu, B., Rabbani, S.A. Demethylation of urokinase (uPA) promoter as a prognostic marker in patients with breast carcinoma. Clin. Cancer Res. 10(9):3035-3041, 2004.
Pakneshan, P., Szyf, M., Farias-Eisner, R., Rabbani, S.A. Reversal of the hypomethylation status of urokinase (uPA) promoter blocks breast cancer growth and metastasis. J. Biol. Chem. 279:31735-31744, 2004.
Shukeir, N., Arakelian, A., Chen, G., Garde, S., Ruiz, M., Panchal, C., Rabbani, S.A. A synthetic 15mer peptide (PCK3145) derived from prostate secretory protein (PSP-94) can reduce tumor growth, experimental skeletal metastases and malignancy associated hypercalcemia. Cancer Res. 64:5370-5377, 2004.
Pakneshan, P., Szyf, M., Rabbani, S.A. Methylation and inhibition of expression of uPA by the RAS oncogene: divergence of growth control and invasion in breast cancer cells. Carcinogenesis 26:557-564, 2005.
Rabbani S.A., Khalili, P., Arakelian, A., Pizzi H., Chen, G., Goltzman, D. Regulation of parathyroid hormone related peptide by estradiol (E2): effect of tumor growth and metastasis in vitro and in vivo. Endocrinology 146:2885-2894, 2005.
Khalili, P., Arakelian, A., Chen, G., Singh, G., Rabbani, S.A. Role of Herceptin in abrogating the progression of skeletal metastases in a xenograft model of human breast cancer. Oncogene 24(44):6657-66, 2005.