Development of a Potential Therapy for Prostate Cancer Based Upon the Androgen Receptor
Our aim is to design targeted therapies which will recognize and disable the androgen receptor when it is activated in the absence androgen.
|Project Leaders||Marianne Sadar|
US Army, Department of Defense
Androgen-independent prostate cancers differ from androgen-responsive prostate cancers as they do not respond to a reduction of male hormone levels, which is one method used to slow the growth of androgen-responsive prostate cancers. Currently, no effective therapies are available for androgen-independent prostate cancer. Therefore, it is critical to identify the molecular mechanisms responsible for the ability of the cancer to grow in the absence of androgen so that new therapies can be developed. Our laboratory recently identified a possible molecular mechanism that may underlie androgen-independent disease. This mechanism builds on pre-existing knowledge that androgen stimulates the growth of prostate cells by activating androgen receptors located in the cell. The activation of the androgen receptor also is linked to the growth of prostate cancer cells and is the basis for androgen withdrawal therapy for patients with prostate cancer. Work in our laboratory has yielded results verifying the existence of alternative mechanisms for activating the androgen receptor in the absence of androgens. We have identified a unique region on the androgen receptor, such that when many copies of this region (called decoy molecules, or ARN) are produced in prostate cancer cells, they specifically prevent androgen-independent increases in prostate-specific antigen. These data provide the rationale for the studies proposed, which include testing whether decoy molecules will prevent or delay the progression of prostate cancer to androgen independence. The problem of how to deliver these therapeutic peptides to patients with systemic prostate cancer is another important area of this research. Through this work we aim to identify new treatments to prevent androgen-independent disease.
Related Publications by our Research Team:
Wang G, Wang J, and Sadar MD. Crosstalk between the androgen receptor and ß-catenin pathways in androgen independent prostate cancer. Cancer Research, 2008 Dec 1;68(23):9918-27.
Sadar MD, Williams DE, Mawji NR, Patrick BO, Chasanah E, Irianto HE, Van Soest R, Andersen RJ. (2008) Sintokamides A to E, chlorinated peptides from the sponge Dysidea sp. that inhibit transactivation of the N-terminus of the androgen receptor in prostate cancer cells. Org. Letts., 2008 Nov 6;10(21):4947-50. Epub 2008 Oct 4.
Lin D, Watahiki A, Zhang F, Liu L, Ling V, Sadar MD, English J, Fazli L, Gleave M, So A, Gout PW Wang Y-Z. ASAP1, a Gene at 8q24, is Associated with Prostate Cancer Metastasis. Cancer Research. 2008 Jun 1;68(11):4352-9.
Myung J-K and Sadar MD. Proteomic research in prostate cancer in Genome Science and Molecular Medicine. Eds, Thangadurai D., Tang W., and Pullaiah T. Regency Publications. In press.
Sadar MD. Role of cAMP in regulating the androgen receptor in Androgen Action in Prostate Cancer. Eds, Tindall DJ and Mohler JL. Springer Publishers. In press.
Quayle SN, Mawji NR, Wang J, Sadar MD. Androgen receptor decoy molecules block the growth of prostate cancer. Proc. Natl. Acad. Sci. USA. 2007 Jan 16: 104(4)1331-1336.
Quayle SN, Sadar MD 14-3-3 sigma increases the transcriptional activity of the androgen receptor in the absence of androgens. Cancer Lett. 2007;254(1):137-45.
For all project related inquires please contact us.
Joanne Johnson, Projects Manager
Genome Sciences Centre, BC Cancer Agency
Phone: (604)675-8150 x 7901