MICaB Graduate Program
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Scott M. Dehm, Ph.D.
Department of Laboratory Medicine & Pathology
University of Saskatchewan, 2003, Ph.D.
Androgen receptor activation in prostate cancer
Research in the Dehm laboratory focuses on the role of the androgen receptor in prostate cancer development and progression. The androgen receptor is a nuclear steroid receptor transcription factor that responds to the physiologic androgens testosterone and dihydrotestosterone. Traditionally, treatment for metastatic prostate cancer has depended on blocking the production or action of these androgens in order to inhibit the growth and survival promoting functions of the androgen receptor. Androgen depletion is therefore one of the earliest examples of targeted cancer therapy. The primary limitation of androgen depletion is that prostate cancer will eventually develop resistance and recur with a lethal castration-resistant phenotype. Our laboratory studies the changes that occur in the therapeutic target (the androgen receptor) in response to the targeted therapy (androgen depletion) to understand the mechanisms underlying this progression to therapy-resistant disease. Our approach is to employ a variety of genomic, molecular biology, and biochemistry tools to study prostate cancer progression in clinical prostate cancer specimens as well as cell- and xenograft-based models of the disease. Our ultimate goal is to develop new AR-targeted therapies that could more effectively and durably suppress prostate cancer growth.
Selected Recent Publications:
- Chan SC, Selth LA, Li Y, Nyquist MD, Miao L, Bradner JE, Raj GV, Tilley WD, Dehm SM. 2015. Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. Nucleic Acids Research, In Press. *Selected as a 2015 “Breakthrough Article” by NAR.
- Brand LJ, Ravindranathan P, Guo H, Kempema AM, Andrews TE, Harki DA, Chen X, Raj GV, Dehm SM. 2015. EPI-001 is a Selective Peroxisome Proliferator-Activated Receptor-Gamma Modulator with Inhibitory Effects on Androgen Receptor Expression and Activity in Prostate Cancer. Oncotarget, 6:3811-24.
- Chan SC and Dehm SM. 2014. Constitutive activity of the androgen receptor. Advances in Pharmacology, 70:327-66.
- Ware KE, Garcia-Blanco MA, Armstrong AJ, Dehm SM. 2014. Biologic and Clinical Significance of Androgen Receptor Variants in Castration Resistant Prostate Cancer. Endocrine Related Cancer, 21:T87-T103.
- Nyquist MD, Li, Y, Hwang TH, Manlove LS, Vessella RL, Silverstein KAT, Voytas DF, Dehm SM. 2013. TALEN-Engineered AR Gene Rearrangements Reveal Endocrine Uncoupling of Androgen Receptor in Prostate Cancer. Proc. Natl. Acad. Sci. USA, 110:17492-7.
- Dehm SM. 2013. Alternatively spliced protein variants: exploiting modularity to outwit cancer therapy. Cancer Research, 73:5309-14.
- Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. 2013. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res., 73:483-9. *one of the top-cited 2013 Cancer Research publications featured in “The Best of the AACR Journals”
- Chan SC, Li Y, Dehm SM. 2012. Androgen receptor splice variants activate AR target genes and support aberrant prostate cancer cell growth independent of the canonical AR nuclear localization signal. J. Biol. Chem., 287:19736-49.
- Li Y, Hwang TH, Oseth LA, Hauge A, Vessella RL, Schmechel SC, Hirsch B, Beckman KB, Silverstein KA, Dehm SM. 2012. AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene, 31:4759-67.
- Li Y, Alsagabi M, Fan D, Bova GS, Tewfik AH, Dehm SM. 2011. Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. Cancer Res. Mar 15;71(6):2108-17.