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.
Yang YC, Meimetis L, Tien AH, Mawji NR, Carr G, Wang J, Andersen RJ, Sadar MD. Spongian diterpenoids inhibit androgen receptor activity. In press, Molecular Cancer Therapeutics.
Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, Tien AH, Yang YC, Tavakoli I, Haile S, Watt K, McEwan IJ, Plymate S, Andersen RJ, Sadar MD. Blocking androgen receptor N-terminal domain to treat advanced prostate cancer. In revision, Journal of Clinical Investigation.
Myung JK and Sadar MD. Large scale phosphoproteome analysis of LNCaP human prostate cancer cells. Molecular Biosystems. 2012 Aug;8(8):2174-82. DOI:10.1039/c2mb25151e.
Meimetis LG, Williams DE, Mawji NR, Banuelos CA, Lal AA, Park JJ, Tien AH, Fernandez JG, de Voogd NJ, Sadar MD, Andersen RJ. Niphatenones, Glycerol Ethers from the Sponge Niphates digitalis Block Androgen Receptor Transcriptional Activity in Prostate Cancer Cells: Structure Elucidation, Synthesis, and Biological Activity. J Med Chem. 2012 Jan 12;55(1):503-14. Faculty of 1000, FFA rating: 6.
Haile S, Lal A, Myung J-K. Sadar MD. FUS/TLS is a co-activator of the androgen receptor in prostate cancer cells. Plos One. 2011;6(9):e24197. 2011 Sep 1[Epub ahead of print].
Sadar MD. Advances in Small Molecule Inhibitors of Androgen Receptor for the Treatment of Advanced Prostate Cancer. World J Urol. 2011 Aug 11 [Epub ahead of print].
Haile S, Sadar MD. Androgen receptor and its splice variants in prostate cancer. Cell Mol Life Sci. 2011 Dec;68(24):3971-81 2011 Jul 12.
Sadar MD. Small Molecules Targeting the “Achilles” Heel of Androgen Receptor Activity. Cancer Research. 2011 Feb 15;71(4):1208-13.
Romanuik TL, Wang G, Morozova O, Delaney A, Marra MA, Sadar MD. LNCaP Atlas: gene expression associated with in vivo progression to castration-recurrent prostate cancer. BMC Medical Genomics, 2010 Sep 24;3:43.
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. Faculty of 1000, FFA rating: 9.
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
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.
Romanuik TL, Wang G, Holt RA, Marra MA, Sadar MD. Identification of novel androgen-responsive genes by deep 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.
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.
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.
Yee J, Sadar MD, Sin DD, Kuzyk M, Xing L, Kondra J, McWilliams A, Man SF, Lam S. Connective tissue-activating peptide III: a novel blood biomarker for early lung cancer detection. J Clin Oncol. 2009 Jun 10;27(17):2787-92. Faculty of 1000, FFA rating: 8.
Wang G, Wang J, and Sadar MD. Crosstalk between the androgen receptor and β-catenin pathways in castrate-resistant 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.
Marianne Sadar's Complete Publication List with links to selected papers.