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Osu1227282252.Pdf (1.38 SELECTIVE ANDROGEN RECEPTOR MODULATOR (SARM) ACTION: ANDROGEN THERAPY REVISITED DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Christopher C Coss, B.S. *** The Ohio State University 2008 Dissertation Committee: Approved by Dr. James T. Dalton, Advisor Dr. Robert W. Brueggemeier _________________________________ Dr. Thomas D. Schmittgen Advisor Dr. Mamuka Kvaratskhelia Pharmacy Graduate Program ABSTRACT Despite continuing advances in the clinical development of selective androgen receptor modulators (SARMs) for male hypogonadism, osteoporosis, muscle wasting and myriad diseases of the prostate, mechanism remains controversial. To date, mechanistic work in the selective hormone receptor modulator (SRM) field has been dominated by selective estrogen receptor modulators (SERMs) where a full understanding of SERM action contributed to the development of second generation molecules with better selectivity and reduced side effects. It follows that a better understanding of SARM action could lead to improvements in rationale SARM design and even molecules tailor made for specific patient populations or disease states. The studies described herein were carried out to shed light on the molecular mechanism of aryl propionamide SARM action resulting in full efficacy in anabolic tissues (muscle and bone), while sparing androgenic tissues (prostate and skin). To this end genome wide androgen receptor (AR) promoter binding and transcriptional profiling in LNCaP prostate cancer cells was performed. In these experiments, the primary prostatic androgen 5α-dihydrostestosterone (DHT) was compared to aryl propionamide SARMs, revealing largely overlapping but distinct modes of action. These works support the existence of qualitative differences, not solely due to potency, underlying SARM mechanism. ii A renewed therapeutic interest in androgens has created an opportunity to re- evaluate side effects that have prevented wide scale androgen therapy. Seemingly pro- athrogenic lipid profiles result from androgen treatment though links to cardiovascular disease are largely observational and conflicting. Also studies showing androgens to be hepatotoxic are confounded by existing disease states and a heavy focus on anabolic steroid abusers. Nevertheless, the dogma surrounding dangers of androgen administration contribute to clinicians’ apprehensions in using anabolic agents to treat a cadre of human ailments. The studies described herein characterize these effects for aryl propionamide SARMs arguing that elevations of serum ALT, thought to reflect liver toxicity, are actually the result of androgen mediated gene expression. Reductions in serum HDL-C were found to be tightly linked with anabolic efficacy in short term studies, but flexibility in the aryl propionamide pharmacophore coupled with high amenability to varied formulations offer hope toward future SARM therapies. iii ACKNOWLEDGMENTS I would like to first and foremost acknowledge my wife Shelley Orwick. Without her endless support, this effort would have failed long ago. I am incredibly fortunate for her caring and infinite patience. I would also like to extend my gratitude to Drs. Wenqing Gao and Ramesh Narayanan for their many lessons. Their teachings greatly shaped my graduate training. I would like to thank Drs. Jeffrey Kearbey and Mitchell A. Phelps for setting me on this course and keeping me on this course, respectively. I would like to thank Dr. Victor Jin for his introduction to bioinformatics. My gratitude is also owed to my committee members Dr. Robert W. Brueggemeier, Dr. Thomas D. Schmittgen and Dr. Mamuka Kvaratskhelia whom provided many useful suggestions. I would also like to thank GTx Inc. for allowing me to continue my graduate research while in their employ. Finally, I would like to convey my appreciation to my advisor Dr. James T. Dalton for the many opportunities- past, present and future. iv VITA February 23, 1980........................Born – Columbus, Ohio 2002.............................................B.S. Molecular Genetics, The Ohio State University B.S. Computer Science, The Ohio State University 2003-2004……………………...Graduate Teaching Assistant, The Ohio State University 2004-2006……………………...Graduate Research Associate, The Ohio State University 2006-present……………………Research Technician, GTx Inc., Memphis, TN PUBLICATIONS Research Publications 1. Gao W, Reiser PJ, Coss CC, Phelps MA, Kearbey JD, Miller DD, Dalton JT. “Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats.” Endocrinology, 146(11):4887-97, 2005. 1. Narayanan R, Coss CC, Yepuru M, Kearbey JD, Miller DD, Dalton JT. “Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S- 22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways.” Molecular Endocrinology, 22(11): 2448-65, 2008. FIELDS OF STUDY Major Field: Pharmacy v TABLE OF CONTENTS Abstract.............................................................................................................................. ii Acknowledgments ............................................................................................................ iv Vita..................................................................................................................................... v Table of Contents.............................................................................................................. vi List of Tables .................................................................................................................... xi List of Figures.................................................................................................................xiii 1. Introduction..................................................................................................................... 1 1.1. Androgens............................................................................................................. 1 1.1.1 Physiological Role and Clinical Utility....................................................... 1 1.1.2 Androgen Receptor – Structure/Function.................................................... 3 1.2. Selective Androgen Receptor Modulators (SARMs) ........................................... 5 1.2.1 Discovery and Characterization of the Aryl Propionamides SARMs ......... 6 1.2.2 SARMs – Therapeutic Promise................................................................... 7 1.2.3 SARMs – Therapeutic Concerns............................................................... 10 1.2.4 SARM Mechanism .................................................................................... 12 1.3. Scope and Objective of Dissertation................................................................... 14 2. SARM versus DHT: Gene Expression Profiling in LNCaP Prostate Cancer Cells...... 23 2.1. Introduction......................................................................................................... 23 2.2. Materials and Methods ....................................................................................... 24 2.2.1 Materials.................................................................................................... 24 2.2.2 LNCaP Cell Growth Curve ....................................................................... 24 2.2.3 AR Trans-activation in COS-1 Cells......................................................... 25 2.2.4 cDNA Microarray Study Design ............................................................... 25 vi 2.2.5 cDNA Microarray Data Analysis .............................................................. 26 2.2.6 Orthologous Promoter Androgen Response Element (ARE) Search........ 27 2.2.7 Gene Expression Validation...................................................................... 29 2.2.8 Electro-Mobility Shift Assay (EMSA)...................................................... 29 2.2.9 Gene Ontology Functional Analyses......................................................... 31 2.3. Results................................................................................................................. 31 2.3.1 LNCaP Growth Curve ............................................................................... 31 2.3.2 Gene Expression Profile............................................................................ 32 2.3.3 Gene Expression Validation...................................................................... 33 2.3.4 Putative Androgen Response Elements..................................................... 33 2.3.5 EMSA Validation of AR Binding Potential .............................................. 34 2.3.6 Functional Analyses .................................................................................. 35 2.4. Discussion........................................................................................................... 36 2.5. Acknowledgments .............................................................................................. 41 3. SARM versus DHT: Genome-wide AR promoter recruitment profiling in LNCaP Prostate Cancer Cells ........................................................................................................ 53 3.1. Introduction......................................................................................................... 53 3.2. Materials and Methods ......................................................................................
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