Donald McDonnell

Overview:

The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of several drugs that are currently being evaluated in the clinic as cancer therapeutics, and to the identification of potential biomarkers and predictors of response that can help to target the use of these new drugs. Most recently we have explored approaches to treat triple negative breast cancer and have identified an important pathway that links obesity/dyslipidemia and cancer risk.

Positions:

Chair, Department of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Glaxo-Wellcome Professor of Molecular Cancer Biology, in the School of Medicine

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Professor in Medicine

Medicine, Endocrinology, Metabolism, and Nutrition
School of Medicine

Core Faculty in Innovation & Entrepreneurship

Duke Innovation & Entrepreneurship
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1988

Baylor College of Medicine

Grants:

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
Awarded By
National Cancer Institute
Role
Mentor
Start Date
End Date

Live-Animal Micro-CT System

Administered By
Orthopaedics
Awarded By
National Institutes of Health
Role
Major User
Start Date
End Date

Identification of actionable networks promoting breast cancer progression and brain metastasis

Administered By
Pharmacology & Cancer Biology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Identification of Novel Targets in Treatment Resistant Prostate Cancer

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
End Date

Publications:

Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERα-dependent and -independent manners.

Lysine specific demethylase 1 (LSD1, also known as KDM1) is a histone modifying enzyme that regulates the expression of many genes important in cancer progression and proliferation. It is present in various transcriptional complexes including those containing the estrogen receptor (ER). Indeed, inhibition of LSD1 activity and or expression has been shown to attenuate estrogen signaling in breast cancer cells in vitro, implicating this protein in the pathogenesis of cancer. Herein we describe experiments that utilize small molecule inhibitors, phenylcyclopropylamines, along with small interfering RNA to probe the role of LSD1 in breast cancer proliferation and in estrogen-dependent gene transcription. Surprisingly, whereas we have confirmed that inhibition of LSD1 strongly inhibits proliferation of breast cancer cells, we have determined that the cytostatic actions of LSD1 inhibition are not impacted by ER status. These data suggest that LSD1 may be a useful therapeutic target in several types of breast cancer; most notably, inhibitors of LSD1 may have utility in the treatment of ER-negative cancers for which there are minimal therapeutic options.
Authors
Pollock, JA; Larrea, MD; Jasper, JS; McDonnell, DP; McCafferty, DG
MLA Citation
Pollock, Julie A., et al. “Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERα-dependent and -independent manners..” Acs Chem Biol, vol. 7, no. 7, July 2012, pp. 1221–31. Pubmed, doi:10.1021/cb300108c.
URI
https://scholars.duke.edu/individual/pub787239
PMID
22533360
Source
pubmed
Published In
Acs Chem Biol
Volume
7
Published Date
Start Page
1221
End Page
1231
DOI
10.1021/cb300108c

The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis.

Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, and the identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydroxycholesterol (27HC), suggests a mechanism by which nutritional/metabolic status can influence bone biology. With its levels directly correlated with cholesterol, a new possibility emerges wherein 27HC links estrogen and cholesterol signaling to bone homeostasis. In these studies, we found that increasing concentrations of 27HC, both by genetic and pharmacological means, led to decreased bone mineral density that was associated with decreased bone formation and increased bone resorption. Upon manipulation of endogenous estrogen levels, many of the responses to elevated 27HC were altered in such a way as to implicate ER as a likely mediator. In a model of postmenopausal bone loss, some pathologies associated with elevated 27HC were exacerbated by the absence of endogenous estrogens, suggesting that 27HC may act both in concert with and independently from classic ER signaling. These data provide evidence for interactions between estrogen signaling, cholesterol and metabolic disease, and osteoporosis. Patients with high cholesterol likely also have higher than average 27HC, perhaps putting them at a higher risk for bone loss and fracture. More studies are warranted to fully elucidate the mechanism of action of 27HC in bone and to identify ways to modulate this pathway therapeutically.
Authors
DuSell, CD; Nelson, ER; Wang, X; Abdo, J; Mödder, UI; Umetani, M; Gesty-Palmer, D; Javitt, NB; Khosla, S; McDonnell, DP
MLA Citation
DuSell, Carolyn D., et al. “The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis..” Endocrinology, vol. 151, no. 8, Aug. 2010, pp. 3675–85. Pubmed, doi:10.1210/en.2010-0080.
URI
https://scholars.duke.edu/individual/pub726825
PMID
20501668
Source
pubmed
Published In
Endocrinology
Volume
151
Published Date
Start Page
3675
End Page
3685
DOI
10.1210/en.2010-0080

Characterization of antiestrogenic activity of the Chinese herb, Prunella vulgaris, using in vitro and in vivo (mouse xenograft) models (Biology of Reproduction 2009, 80, (375-383) DOI: 10.1095/biolreprod.107.065375)

Authors
Collins, NH; Lessey, EC; DuSell, CD; McDonnell, DP; Fowler, L; Palomino, WA; Illera, MJ; Yu, X; Mo, B; Houwing, AM; Lessey, BA
URI
https://scholars.duke.edu/individual/pub787486
Source
scopus
Published In
Biology of Reproduction
Volume
80
Published Date
Start Page
1306
DOI
10.1095/biolreprod.109.078303

Molecular pharmacology of estrogen and progesterone receptors

This chapter provides an update on the mechanisms of action of estrogen and progesterone. Particularly important concepts include nongenomic effects, receptor isoforms that affect agonist/antagonist actions, and the role of coactivators and corepressors in various tissues. The steroid hormones estrogen and progesterone are low-molecular weight, lipophilic hormones that through their action as modulators of distinct signal transduction pathways, are involved in the regulation of reproductive function. These hormones are also important regulators in bone, the cardiovascular system, and the central nervous system. Despite their different roles in these systems, it has become apparent that estrogens and progestins are mechanistically similar. Insights gleaned from the study of each hormone have advanced the understanding of this class of molecules as a whole. Some of the recent mechanistic discoveries that have occurred in the field are highlighted and the subsequent changes in our understanding of the pharmacology of this class of steroid hormones are explored. © 2007 Elsevier Inc. All rights reserved.
Authors
Sherk, AB; McDonnell, DP
MLA Citation
Sherk, A. B., and D. P. McDonnell. Molecular pharmacology of estrogen and progesterone receptors. Dec. 2007, pp. 17–28. Scopus, doi:10.1016/B978-012369443-0/50004-1.
URI
https://scholars.duke.edu/individual/pub965330
Source
scopus
Published Date
Start Page
17
End Page
28
DOI
10.1016/B978-012369443-0/50004-1

Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators.

We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles.
Authors
Kazmin, D; Prytkova, T; Cook, CE; Wolfinger, R; Chu, T-M; Beratan, D; Norris, JD; Chang, C-Y; McDonnell, DP
MLA Citation
Kazmin, Dmitri, et al. “Linking ligand-induced alterations in androgen receptor structure to differential gene expression: a first step in the rational design of selective androgen receptor modulators..” Mol Endocrinol, vol. 20, no. 6, June 2006, pp. 1201–17. Pubmed, doi:10.1210/me.2005-0309.
URI
https://scholars.duke.edu/individual/pub672749
PMID
16574741
Source
pubmed
Published In
Molecular Endocrinology (Baltimore, Md.)
Volume
20
Published Date
Start Page
1201
End Page
1217
DOI
10.1210/me.2005-0309

Research Areas:

3T3 Cells
8-Bromo Cyclic Adenosine Monophosphate
ADP-ribosyl Cyclase 1
Acetates
Acetyl Coenzyme A
Acetyltransferases
Adolescent
Adult
Age Factors
Aging
Aldehyde Dehydrogenase
Allosteric Regulation
Amino Acid Motifs
Amino Acid Sequence
Androgen Receptor Antagonists
Androgens
Antigens, CD
Antigens, CD38
Antigens, Nuclear
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Apoptosis
Aromatase
Aryl Hydrocarbon Receptor Nuclear Translocator
Atlases as Topic
Autocrine Communication
Benzhydryl Compounds
Benzoates
Binding Sites
Biological Transport
Biomimetic Materials
Blotting, Western
Bone and Bones
Breast
Breast Neoplasms
Bruch Membrane
COS Cells
Cadherins
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Carcinoma, Hepatocellular
Cardiovascular System
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Cercopithecus aethiops
Chemokine CXCL12
Child
Cholestanetriol 26-Monooxygenase
Cholesterol
Cholesterol Side-Chain Cleavage Enzyme
Chromans
Chromatin
Chromatin Immunoprecipitation
Chrysenes
Cinnamates
Cluster Analysis
Combinatorial Chemistry Techniques
Consensus Sequence
Cytoprotection
DNA Primers
DNA-Binding Proteins
Dehydroepiandrosterone
Dieldrin
Diethylstilbestrol
Dose-Response Relationship, Drug
Down-Regulation
Drug Design
Drug Discovery
Drug Evaluation, Preclinical
Drug Interactions
Drug Partial Agonism
Drug Resistance
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Drug Synergism
E2F1 Transcription Factor
Enhancer Elements, Genetic
Enzyme Activation
Enzyme Inhibitors
Enzyme-Linked Immunosorbent Assay
Estradiol
Estradiol Antagonists
Estradiol Congeners
Estrenes
Estriol
Estrogen Antagonists
Estrogen Receptor Modulators
Estrogen Receptor alpha
Estrogen Receptor beta
Estrogen Replacement Therapy
Estrogens
Estrogens, Non-Steroidal
Estrone
Extracellular Matrix
Female
Flow Cytometry
Furylfuramide
Gene Expression
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Gene Library
Genes, Reporter
Glucose
Glucose Transporter Type 1
Gonadal Steroid Hormones
Green Fluorescent Proteins
HCT116 Cells
HEK293 Cells
Haplorhini
HeLa Cells
Heat-Shock Proteins
Hematopoiesis
Hepatocyte Nuclear Factor 4
Hexokinase
Histone Acetyltransferases
Histone Deacetylase Inhibitors
Homeodomain Proteins
Hormone Antagonists
Humans
Hydroxycholesterols
Hydroxymethylglutaryl-CoA Synthase
Immunoblotting
Immunohistochemistry
Immunosuppressive Agents
Indoles
Induced Pluripotent Stem Cells
Inflammatory Breast Neoplasms
Insecticides
Insulin-Like Growth Factor I
Interleukin-1beta
Intracellular Signaling Peptides and Proteins
Kruppel-Like Transcription Factors
Leupeptins
Ligands
Lipofuscin
Lipoproteins, LDL
Locus Coeruleus
MCF-7 Cells
MSX1 Transcription Factor
Macrophages
Macular Degeneration
Male
Mammary Glands, Human
Metribolone
Mice
Mice, Congenic
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, Nude
Mice, SCID
Mice, Transgenic
Microscopy, Electron
Middle Aged
Mifepristone
Mitochondria
Mitogen-Activated Protein Kinases
Molecular Conformation
Molecular Sequence Data
Molecular Targeted Therapy
Multiple Myeloma
Mutagenesis, Site-Directed
NF-kappa B
Norepinephrine
Nuclear Receptor Co-Repressor 1
Nuclear Receptor Co-Repressor 2
Nuclear Receptor Coactivator 1
Nuclear Receptor Coactivator 2
Nuclear Receptor Coactivators
Organ Size
Orphan Nuclear Receptors
Osteoblasts
Osteoclasts
Osteogenesis
Osteoporosis
Ovariectomy
Oxidation-Reduction
PPAR gamma
Peptide Library
Peroxidase
Peroxisome Proliferator-Activated Receptors
Phenols
Pigment Epithelium of Eye
Plicamycin
Polymerase Chain Reaction
Progesterone
Progestins
Promegestone
Promoter Regions, Genetic
Prostate-Specific Antigen
Prostatic Neoplasms
Protein Conformation
Protein Kinase Inhibitors
Protein Kinases
Protein Stability
Protein Structure, Secondary
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases
Proteins
Proteolysis
RNA Interference
RNA, Messenger
RNA, Small Interfering
RNA-Binding Proteins
Raloxifene
Raloxifene Hydrochloride
Rats
Rats, Sprague-Dawley
Rats, Wistar
Reactive Oxygen Species
Receptor Cross-Talk
Receptor, IGF Type 1
Receptor, erbB-2
Receptors, Androgen
Receptors, Aryl Hydrocarbon
Receptors, CXCR4
Receptors, Calcitriol
Receptors, Cytoplasmic and Nuclear
Receptors, Estrogen
Receptors, Glucocorticoid
Receptors, Progesterone
Receptors, Retinoic Acid
Receptors, Steroid
Recombinant Fusion Proteins
Recombinant Proteins
Repetitive Sequences, Nucleic Acid
Repressor Proteins
Response Elements
Retinal Dehydrogenase
Retinal Pigment Epithelium
Retinoblastoma Protein
Retinoid X Receptor alpha
Retinoid X Receptors
Retinoids
Reverse Transcriptase Polymerase Chain Reaction
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Selective Estrogen Receptor Modulators
Sequence Deletion
Species Specificity
Stem Cell Transplantation
Steroid 17-alpha-Hydroxylase
Steroid Hydroxylases
Steroids
Stilbenes
Structure-Activity Relationship
T-Lymphocytes
Tacrolimus Binding Proteins
Tamoxifen
Thiazolidinediones
Tight Junctions
Toxaphene
Trans-Activators
Transcription Factor AP-1
Transcription Factors
Transcription, Genetic
Transcriptional Activation
Transfection
Translocation, Genetic
Tretinoin
Tumor Burden
Two-Hybrid System Techniques
Ubiquitin-Protein Ligase Complexes
Ubiquitin-Protein Ligases
Up-Regulation
Uterus
Vascular Endothelial Growth Factor A
Wnt Proteins
Young Adult
beta Catenin