Sadar, Marianne D.
Associate Member, Dept of Pathology and Laboratory Medicine
Assistant Professor, Dept of Surgery
Program Leader for Prostate Cancer Research, British Columbia Cancer Agency
B.Sc. (Biochemistry), Simon Fraser University
Ph.D. (Biochemistry), University of Bradford, U.K. (1995)
ESF Doctoral Fellow (Toxicology), University of Goteborg, Sweden (1993)
Post-doctoral Fellow (Molecular Biology), Astra Hassle, Molndal, Sweden (1995)
Research Interests
The major focus of my research is to develop therapies that will delay or prevent tumour progression and the emergence of androgen independence in prostate cancer. Current treatment for progressed prostate cancer is androgen withdrawal. While initially effective this treatment is unable to completely and permanently eliminate all prostate cancer cell populations. After a predictable initial response to treatment, there is a relapse as the cancer progresses to an androgen-independent stage. An early sign of progression to androgen-independence, related to reduced survival, is a rising titre of serum prostate-specific antigen (PSA) after an initial response to androgen deprivation. The transcriptional regulation of the PSA gene has been shown to correlate well with the progression of prostate cancer, with both gene expression and the disease going from an androgen-dependent to an androgen-independent stage. Thus the major objective of one area of my research is to identify the molecular mechanisms involved in the progression of prostate cancer to androgen independence. To do this, I am presently characterising the regulation of PSA gene expression both in the presence, and in the absence of androgen.
Through the investigation of PSA gene expression, I have considered that the anomalous expression of the PSA gene may involve alternative signal transduction pathways which act to either bypass the androgen receptor or result in its activation in the absence of androgen. Recently, I have shown that indeed the androgen receptor can be activated in the absence of androgen through cross-talk with the cAMP-dependent protein kinase (PKA) pathway. This mechanism may prove to be important in the progression of prostate cancer to androgen independence. Therefore, I am mapping the region of the androgen receptor that is required for androgen-independent activation and developing molecular recognition peptide sequences to be used for therapeutic treatment for advanced prostate cancer.
To identify the molecular events involved in the progression of prostate cancer, I have developed a murine model using human prostate cancer cells. This model enables the retrieval of homogenous populations of cells that has allowed me to perform molecular analysis on cells harvested from animals during different stages of progression. These studies have identified new molecular therapeutic targets that are currently being evaluated.
The most common site of secondary prostate cancer malignancy is the bone. Therefore I am currently investigating interactions between prostate cancer cells and bone which results in the proliferation of both prostate cancer cells and bone osteoblasts. Inhibiting the interaction of these osteoblast-specific factors with metastatic prostate cancer cells may prevent or delay the progression of prostate cancer cells to androgen independence, alleviate the severe pain often associated with new bone formation and provide a better quality of life for those prostate cancer patients with bone metastases.
Selected Publications
Meehan, K.L. and Sadar, M.D. (2004) Quantitative profiling of LNCaP prostate cancer cells using isotope-coded affinity tags and mass spectrometry. Proteomics, 4, 1116-1134.
Blaszczyk, N., Masri, B., Mawji, N.R., Ueda, T., McAlinden, G., Duncan, C.P., Bruchovsky, N., Schweikert, H.U., Schnabel, D., Jones, E.C. and Sadar, M.D. (2004) Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells. Clinical Cancer Research 10, 1860-1869.
Meehan, K.L. and Sadar, M.D. (2003) Androgens and androgen receptor in prostate and ovarian malignancies. Frontiers in Bioscience, 8, 780-800.
Ueda, T., Mawji, N.R., Bruchovsky, N., and Sadar, M. (2002) Ligand-independent activation of the androgen receptor and the role of the coactivator SRC-1a in prostate cancer cells. J. Biol. Chem., 277, 38087-38094.
Sadar, M.D., Akopian, V., and Beraldi, E. (2002) Characterization of a new in vivo hollow fiber model for the study of progression of prostate cancer to androgen independence. Molec. Cancer Therap., 1, 629-637.
Ueda, T., Bruchovsky, N., and Sadar, M.D. (2002) Activation of the N-terminus of the androgen receptor by interleukin-6 via MAPK and STAT3 signal transduction pathways cells. J. Biol. Chem., 277, 7076-7085.
Bruchovsky, N., Goldenberg, S.L., Mawji, N.R., and Sadar, M.D. (2001) Evolving aspects of intermittent androgen blockage for prostate cancer: diagnosis and treatment of early tumor progression and maintenance of remission. In, Andrology in the 21st Century, Proceedings of the VIIth International Congress of Andrology, Robaire, B., Chemes, H., and Morales, C.R. (eds), pp. 609-623. Medimond Inc.