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 Distinguished 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:

The Role of Epigenetic Plasticity in Breast Cancer Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

Targeting precursor neural (N)-cadherin to eliminate chemotherapy-resistant triple-negative breast tumor cells

Administered By
Surgery, Plastic, Maxillofacial, and Oral Surgery
Awarded By
Department of Defense
Role
Co Investigator
Start Date
End Date

A Novel Function for ALK4 in Suppressing Breast Cancer Progression

Administered By
Medicine, Medical Oncology
Role
Co-Mentor
Start Date
End Date

Nonclassical signaling of the androgen receptor polyproline domain

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

G Protein Involvement in Oncogenesis and Metastasis

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Consultant
Start Date
End Date

Publications:

Correction to: Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

The article Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy, written by Suzanne E. Wardell, Alexander P. Yllanes, Christina A. Chao, Yeeun Bae, Kaitlyn J. Andreano, Taylor K. Desautels, Kendall A. Heetderks, Jeremy T. Blitzer, John D. Norris, Donald P. McDonnell, was originally published electronically on the publisher's internet portal on September 27, 2019 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on November 16, 2019 to © The Author(s) 2019 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The original article has been corrected.
Authors
Wardell, SE; Yllanes, AP; Chao, CA; Bae, Y; Andreano, KJ; Desautels, TK; Heetderks, KA; Blitzer, JT; Norris, JD; McDonnell, DP
URI
https://scholars.duke.edu/individual/pub1421461
PMID
31734822
Source
pubmed
Published In
Breast Cancer Res Treat
Published Date
DOI
10.1007/s10549-019-05498-0

Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy.

PURPOSE: Fulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patient tumors. By modeling human exposures in animal models we probe the absolute need for SERD activity. METHODS: Three xenograft models of endocrine therapy-resistant breast cancer were used to evaluate the efficacy of fulvestrant administered in doses historically used in preclinical studies in the field or by using a dose regimen intended to model clinical exposure levels. Pharmacokinetic and pharmacodynamic analyses were conducted to evaluate plasma exposure and intratumoral ER downregulation. RESULTS: A clinically relevant 25 mg/kg dose of fulvestrant exhibited antitumor efficacy comparable to the historically used 200 mg/kg dose, but at this lower dose it did not result in robust ER downregulation. Further, the antitumor efficacy of the lower dose of fulvestrant was comparable to that observed for other oral SERDs currently in development. CONCLUSION: The use of clinically unachievable exposure levels of fulvestrant as a benchmark in preclinical development of SERDs may negatively impact the selection of those molecules that are advanced for clinical development. Further, these studies suggest that antagonist efficacy, as opposed to SERD activity, is likely to be the primary driver of clinical response.
Authors
Wardell, SE; Yllanes, AP; Chao, CA; Bae, Y; Andreano, KJ; Desautels, TK; Heetderks, KA; Blitzer, JT; Norris, JD; McDonnell, DP
URI
https://scholars.duke.edu/individual/pub1415058
PMID
31562570
Source
pubmed
Published In
Breast Cancer Res Treat
Published Date
DOI
10.1007/s10549-019-05454-y

The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways.

Mining of integrated public transcriptomic and ChIP-Seq (cistromic) datasets can illuminate functions of mammalian cellular signaling pathways not yet explored in the research literature. Here, we designed a web knowledgebase, the Signaling Pathways Project (SPP), which incorporates community classifications of signaling pathway nodes (receptors, enzymes, transcription factors and co-nodes) and their cognate bioactive small molecules. We then mapped over 10,000 public transcriptomic or cistromic experiments to their pathway node or biosample of study. To enable prediction of pathway node-gene target transcriptional regulatory relationships through SPP, we generated consensus 'omics signatures, or consensomes, which ranked genes based on measures of their significant differential expression or promoter occupancy across transcriptomic or cistromic experiments mapped to a specific node family. Consensomes were validated using alignment with canonical literature knowledge, gene target-level integration of transcriptomic and cistromic data points, and in bench experiments confirming previously uncharacterized node-gene target regulatory relationships. To expose the SPP knowledgebase to researchers, a web browser interface was designed that accommodates numerous routine data mining strategies. SPP is freely accessible at https://www.signalingpathways.org .
Authors
Ochsner, SA; Abraham, D; Martin, K; Ding, W; McOwiti, A; Kankanamge, W; Wang, Z; Andreano, K; Hamilton, RA; Chen, Y; Hamilton, A; Gantner, ML; Dehart, M; Qu, S; Hilsenbeck, SG; Becnel, LB; Bridges, D; Ma'ayan, A; Huss, JM; Stossi, F; Foulds, CE; Kralli, A; McDonnell, DP; McKenna, NJ
MLA Citation
Ochsner, Scott A., et al. “The Signaling Pathways Project, an integrated 'omics knowledgebase for mammalian cellular signaling pathways..” Sci Data, vol. 6, no. 1, Oct. 2019. Pubmed, doi:10.1038/s41597-019-0193-4.
URI
https://scholars.duke.edu/individual/pub1417955
PMID
31672983
Source
pubmed
Published In
Scientific Data
Volume
6
Published Date
Start Page
252
DOI
10.1038/s41597-019-0193-4

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.
Authors
Cocce, KJ; Jasper, JS; Desautels, TK; Everett, L; Wardell, S; Westerling, T; Baldi, R; Wright, TM; Tavares, K; Yllanes, A; Bae, Y; Blitzer, JT; Logsdon, C; Rakiec, DP; Ruddy, DA; Jiang, T; Broadwater, G; Hyslop, T; Hall, A; Laine, M; Phung, L; Greene, GL; Martin, L-A; Pancholi, S; Dowsett, M; Detre, S; Marks, JR; Crawford, GE; Brown, M; Norris, JD; Chang, C-Y; McDonnell, DP
MLA Citation
Cocce, Kimberly J., et al. “The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer..” Cell Rep, vol. 29, no. 4, Oct. 2019, pp. 889-903.e10. Pubmed, doi:10.1016/j.celrep.2019.09.032.
URI
https://scholars.duke.edu/individual/pub1416479
PMID
31644911
Source
pubmed
Published In
Cell Reports
Volume
29
Published Date
Start Page
889
End Page
903.e10
DOI
10.1016/j.celrep.2019.09.032

Combination mTORC1/2 and BCL- XL inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer.

Authors
Sammons, S; Anderson, G; Wardell, S; McDonnell, DP; Marcom, PK; Wood, K
MLA Citation
Sammons, Sarah, et al. “Combination mTORC1/2 and BCL- XL inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer..” Journal of Clinical Oncology, vol. 37, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2019, pp. e14653–e14653. Crossref, doi:10.1200/jco.2019.37.15_suppl.e14653.
URI
https://scholars.duke.edu/individual/pub1415228
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
37
Published Date
Start Page
e14653
End Page
e14653
DOI
10.1200/jco.2019.37.15_suppl.e14653

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