Research Interests

• Prostate cancer

• Drug Development

• Transcriptional regulation

The major focus of my research is to develop therapies that will delay or prevent tumour progression and emergence of hormone independence in prostate cancer. Current treatment for the onset of early stages of prostate cancer is the removal of male hormones, also called androgens, by either drug or surgical treatments. While initially effective in reducing cancer symptoms and PSA levels, this treatment is unable to completely and permanently eliminate all prostate cancer cells. After a predictable initial response to treatment, there is a relapse as the cancer progresses to a more aggressive androgen-independent stage. An early sign of progression to androgen independence, related to reduced survival, is the reappearance of elevated serum levels of PSA. The proteins that regulate the expression of the PSA gene have 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. One of these proteins is the one that actually recognizes and interacts directly with androgens and is called the androgen receptor. Thus the major objective of one area of my research program is to identify the molecular mechanisms that orchestrate the behaviour of proteins such as the androgen recptor during the progression of prostate cancer to androgen independence. To do this, I am presently characterising how these proteins affect the regulation of PSA gene expression both in the presence, and in the absence of androgen.

The results of our PSA gene expression experiments have resulted led to a hypothesis which suggests that the anomalous expression of the PSA gene may involve alternative regulatory 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 by interacting with other proteins in the cAMP-dependent protein kinase (PKA) pathway. These interactions 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 that interfere with these activating interactions. The goal is to utilize these peptides for therapeutic treatment for reversing or preventing advanced prostate cancer.

Recently, to identify the molecular events involved in the progression of prostate cancer, I developed a unique mouse model that allowed me to grow and recover homogenous populations of human prostate cancer cells. This model has allowed me to perform molecular analysis on cells harvested from animals during different stages of progression. These studies have already identified new molecular targets that are currently being evaluated for therapeutic potential.

The most common site of secondary prostate cancer malignancy is the bone. Unlike most other cancers which destroy bone when they metastasize to this tissue, prostate cancer cells actually cause new bone growth by the promotion of cells called osteoblasts. 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

Sadar MD. Small Molecules Targeting the “Achilles” Heel of Androgen Receptor Activity. In Press. Cancer Research 

Lin D, Bayani J, Wang Y, Sadar MD, Yoshimoto M, Gout GW, Squire JA, Wang YZ. Development of metastatic and non-metastatic tumor lines from a patient’s prostate cancer specimen-Identification of a small subpopulation with metastatic potential in the primary tumor. The Prostate 2010 Nov 1;70(15):1636-44

Romanuik TL, Marra MA, Sadar MD. Long serial analysis of gene expression of hormonal progression of prostate cancer to androgen independence. BMC Medical Genomics, 2010 Sep 24;3:43.

Chiu HHL, Yong TMK, Wang J, Wang Y, Vessella RL, Ueda T, Wang YZ, Sadar MD. Induction of Neuronal Apoptosis Inhibitory Protein Expression in Response to Androgen Deprivation in Prostate Cancer. Cancer Letters, 2010 Jun 28;292(2):176-85.

Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T, Yang YC, Banuelos AC, Williams DE, McEwan IJ, Wang YZ, Sadar MD. Regression of castrate-recurrent prostate cancer by a small molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 2010 Jun 15;17(6)535-46.

Romanuik TL, Wang G, Holt RA, Jones SJ, Marra MA, Sadar MD. Identification of novel androgen-responsive genes by sequencing of LongSAGE libraries. BMC Genomics. 2009 Oct 15;10:476.

Romanuik TL, Ueda T, Le N, Haile S, Yong TMK, Thomson T, Vessella RL, Sadar MD. Novel biomarkers for prostate cancer including non-coding transcripts. Am J Pathol. 2009 Dec;175(6):2264-76.

Yee J, Sadar MD, Sin DD, Kuzyk M, Xing L, Rattenbury J, McWilliams A, Man SFP, Lam S. Connective tissue-activating peptide III: a novel blood biomarker for early lung cancer detection.. J Clinical Oncology, 2009 Jun 10;27(17):2787-92. Epub 2009 May 4.

Wang G, Haile S, Comuzzi B, Tien AH, Wang J, Yong TMK, Jelescu-Bodos AE, Blaszczyk N., Vessella RL, Masri B, and Sadar MD. Osteoblast-derived factors induce an expression signature that identifies prostate cancer metastasis and hormonal progression. Cancer Research, 2009 Apr 15;69(8):3433-42.

Sadar MD. Role of cAMP in regulating the androgen receptor in Androgen Action in Prostate Cancer. Eds, Tindall DJ and Mohler JL. Springer Publishers. 2009. pp 465-506.

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.

Wang G, Jones SJM, Marra MA, Sadar MD. Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006  25, 7311-7323.

Quayle SN, Sadar MD. A truncated isoform of TMEFF2 encodes a secreted protein in prostate cancer cells. Genomics. 2006 May;87(5):633-7. Epub 2006 Jan 24.

Le L, Chi K, Tyldesley S, Flibotte S, Diamond DL, Kuzyk MA, Sadar MD. Identification of serum amyloid A as a biomarker to distinguish prostate cancer patients with bone lesions. Clin Chem. 2005 Apr;51(4):695-707. Epub 2005 Feb 3. Citations: 44

Sobel RE, Sadar MD. Cell lines used in prostate cancer research: a compendium of old and new lines--part 2. J Urol. 2005 Feb;173(2):360-72. Citations: 48

Sobel RE, Sadar MD. Cell lines used in prostate cancer research: a compendium of old and new lines--part 1. J Urol. 2005 Feb;173(2):342-59. Citations: 26

Meehan KL, Sadar MD. Quantitative profiling of LNCaP prostate cancer cells using isotope-coded affinity tags and mass spectrometry. Proteomics. 2004 Apr;4(4):1116-34. Citations: 25

Blaszczyk N, Masri BA, Mawji NR, Ueda T, McAlinden G, Duncan CP, Bruchovsky N, Schweikert HU, Schnabel D, Jones EC, Sadar MD. Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells. Clin Cancer Res. 2004 Mar 1;10(5):1860-9. Citations: 15

Meehan KL, Sadar MD. Androgens and androgen receptor in prostate and ovarian malignancies. Front Biosci. 2003 May 1;8:d780-800.

Ueda T, Mawji NR, Bruchovsky N, Sadar MD. Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem. 2002 Oct 11;277(41):38087-94. Epub 2002 Aug 5. Citations: 88

Marianne Sadar's Complete Publication List with links to selected papers.

Patents:

Lam S, Yee J, Kuzyk M, Sin D, Sadar MD, Tammemagi CM.  Novel methods for early detection of lung cancer and monitoring treatment response. PCT/CA2008/002070. License negotiation with Medbiogene

Sadar MD, Mawji NR, Wang J, Andersen R, Williams D, LeBlanc M.  Diglycidic ether derivative therapeutics and methods for their use.  PCT/CA2009/000902. Licensed to ESSA Pharma Inc.

Williams DE, Mawji N, O. Patrick B, Ekowati, Van Soest R, Sadar MD, Andersen RJ. Small molecule inhibitors of N-terminus activation of the androgen receptor.  PCT/CA2009/001173. Licensed to ESSA Pharma Inc.

Sadar MD, Mawji, NR. Peptide inhibitors of androgen-independent activation of androgen receptor. PCT/CA1999/000604

Sadar, MD.; Mawji, NR.; Banuelos, CA; Andersen, RJ.; Garcia Fernandez, J. Achiral Group Containing Bisphenol Derivative Therapeutics And Methods For Their Use. USA Provisional filed Jan. 6, 2010, Full PCT filed Jan 2011. Licensed to ESSA Pharma Inc.

Sadar, MD.; Mawji, NR.; Banuelos, CA; Andersen, RJ.; Garcia Fernandez, J. Bisphenol derivative therapeutics and methods for their use. USA Provisional filed Jan. 6, 2010, Full PCT filed Jan 2011. Licensed to ESSA Pharma Inc.

Sadar MD. Combination therapy uses for certain androgen receptor blocking compounds. U.S. Provisional patent application Filed at the USPTO in Sept, 2010. Licensed to ESSA Pharma Inc.

Sadar MD, Quayle SN, Hare H. Biomarkers and Methods for the Prognosis of Androgen-Independent Prostate Cancer. U.S. Provisional patent application Filed at the USPTO in March, 2009.