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:

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

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1988

Baylor College of Medicine

Grants:

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

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

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Participating Faculty Member
Start Date
End Date

Pharmacology Industry Internships for Ph.D. Students

Administered By
Pharmacology & Cancer Biology
Awarded By
American Society for Pharmacology and Experimental Therapeutics
Role
Participating Faculty Member
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

Publications:

Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.

Immune checkpoint inhibitors (ICB) have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, gender specific differences in response to ICB have been observed with males getting more benefit than females, although the mechanism(s) underlying this difference are unknown. Mining published transcriptomic datasets, we determined that response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor (ERα) stimulate melanoma growth in murine models by skewing macrophage polarization towards an immune-suppressive state that promotes CD8+ T cell dysfunction/exhaustion and ICB resistance. This activity was not evident in mice harboring a macrophage specific depletion of ERα confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD) decreases tumor growth, stimulates adaptive immunity and increases the antitumor efficacy of ICBs. Further, a gene signature that reads on ER activity in macrophages predicted survival in ICB treated melanoma patients. These results highlight the importance of E2/ER as a regulator of intratumoral macrophage polarization; an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.
Authors
Chakraborty, B; Byemerwa, J; Shepherd, JH; Haines, CN; Baldi, R; Gong, W; Liu, W; Mukherjee, D; Artham, S; Lim, F; Bae, Y; Brueckner, O; Heetderks, K; Wardell, SE; Hanks, BA; Perou, CM; Chang, C-Y; McDonnell, DP
MLA Citation
Chakraborty, Binita, et al. “Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.J Clin Invest, Oct. 2021. Pubmed, doi:10.1172/JCI151347.
URI
https://scholars.duke.edu/individual/pub1498834
PMID
34637400
Source
pubmed
Published In
J Clin Invest
Published Date
DOI
10.1172/JCI151347

Mechanistic Investigation of Site-specific DNA Methylating Agents Targeting Breast Cancer Cells.

We previously described the development of a DNA-alkylating compound that showed selective toxicity in breast cancer cells. This compound contained an estrogen receptor α (ERα)-binding ligand and a DNA-binding/methylating component that could selectively methylate the N3-position of adenines at adenine-thymine rich regions of DNA. Herein, we describe mechanistic investigations that demonstrate that this class of compounds facilitate the translocation of the ERα-compound complex to the nucleus and induce the expression of ERα target genes. We confirm that the compounds show selective toxicity in ERα-expressing cells, induce ERα localization in the nucleus, and verify the essential role of ERα in modulating the toxicity. Minor alterations in the compound structure significantly affects the DNA binding ability, which correlates to the DNA-methylating ability. These studies demonstrate the utility of DNA-alkylating compounds to accomplish targeted inhibition of the growth of specific cancer cells; an approach that may overcome shortcomings of currently used chemotherapy agents.
Authors
Lowder, LL; Powell, M; Miller, SE; Kishton, RJ; Kelly, CB; Cribb, CB; Mastro-Kishton, K; Chelvanambi, M; Do, PT; Govindapur, RR; Wardell, SE; McDonnell, DP; Bartolotti, LJ; Akkaraju, GR; Frampton, AR; Varadarajan, S
MLA Citation
Lowder, Leah L., et al. “Mechanistic Investigation of Site-specific DNA Methylating Agents Targeting Breast Cancer Cells.Journal of Medicinal Chemistry, vol. 64, no. 17, Sept. 2021, pp. 12651–69. Epmc, doi:10.1021/acs.jmedchem.1c00615.
URI
https://scholars.duke.edu/individual/pub1494689
PMID
34415160
Source
epmc
Published In
Journal of Medicinal Chemistry
Volume
64
Published Date
Start Page
12651
End Page
12669
DOI
10.1021/acs.jmedchem.1c00615

Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.

Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death.
Authors
Liu, W; Chakraborty, B; Safi, R; Kazmin, D; Chang, C-Y; McDonnell, DP
MLA Citation
Liu, Wen, et al. “Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer.Nat Commun, vol. 12, no. 1, Aug. 2021, p. 5103. Pubmed, doi:10.1038/s41467-021-25354-4.
URI
https://scholars.duke.edu/individual/pub1494688
PMID
34429409
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
5103
DOI
10.1038/s41467-021-25354-4

Current and emerging estrogen receptor-targeted therapies for the treatment of breast cancer.

Nearly 80% of all breast cancers are estrogen receptor positive (ER+) and require the activity of this transcription factor for tumor growth and survival. Thus, endocrine therapies, which target the estrogen signaling axis, have and will continue to be the cornerstone of therapy for patients diagnosed with ER+ disease. Several inhibitors of ER activity exist, including aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders/down-regulators (SERDs), and ER proteolysis-targeting chimeras (ER PROTACs); drugs which differ in the mechanism(s) by which they inhibit this signaling pathway. Notwithstanding their significant impact on the management of this disease, resistance to existing endocrine therapies remains a major impediment to durable clinical responses. Although the mechanisms of resistance are complex and varied, dependence on ER is typically retained after progression on SERMs and AIs, suggesting that ER remains a bona fide therapeutic target. The discovery and development of orally bioavailable drugs that eliminate ER expression (SERDs and ER PROTACs) will likely aid in treating this growing patient population. All of the existing endocrine therapies were developed with the intent of inhibiting the cancer cell intrinsic actions of ER and/or with the objective of achieving extreme estrogen deprivation and most achieve that goal. A longstanding question that remains to be addressed, however, is how actions of existing interventions extrinsic to the cancer cells influence tumor biology. We believe that these issues need to be addressed in the development of strategies to develop the next generation of ER-modulators optimized for positive activities in both cancer cells and other cells within the tumor microenvironment (TME).
Authors
Haines, CN; Wardell, SE; McDonnell, DP
MLA Citation
Haines, Corinne N., et al. “Current and emerging estrogen receptor-targeted therapies for the treatment of breast cancer.Essays Biochem, July 2021. Pubmed, doi:10.1042/EBC20200174.
URI
https://scholars.duke.edu/individual/pub1493387
PMID
34328178
Source
pubmed
Published In
Essays Biochem
Published Date
DOI
10.1042/EBC20200174

Next-Generation Endocrine Therapies for Breast Cancer.

Authors
McDonnell, DP; Wardell, SE; Chang, C-Y; Norris, JD
MLA Citation
McDonnell, Donald P., et al. “Next-Generation Endocrine Therapies for Breast Cancer.Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 39, no. 12, Apr. 2021, pp. 1383–88. Epmc, doi:10.1200/jco.20.03565.
URI
https://scholars.duke.edu/individual/pub1476069
PMID
33705209
Source
epmc
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
39
Published Date
Start Page
1383
End Page
1388
DOI
10.1200/jco.20.03565

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