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

Professor of Cell Biology

Cell Biology
School of Medicine

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

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
Awarded By
Susan G. Komen Breast Cancer Foundation
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:

Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells.

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) cells but is upregulated in tumor-infiltrating NK cells where it suppresses apoptosis and promotes proliferation. NK cell-intrinsic deletion of CaMKK2 increased metastatic progression in several murine models, establishing a critical role for this enzyme in NK cell-mediated antitumor immunity. Ablation of the CaMKK2 protein, but not inhibition of its kinase activity, resulted in decreased NK-cell survival. These results indicate an important scaffolding function for CaMKK2 in NK cells and suggest that competitive CaMKK2 inhibitors and ligand-directed degraders (LDD) are likely to have distinct therapeutic utilities. Finally, we determined that intracellular lactic acid is a key driver of CaMKK2 expression, suggesting that upregulated expression of this enzyme is an adaptive mechanism by which tumor-infiltrating NK cells mitigate the deleterious effects of a lactic acid-rich tumor microenvironment. The findings of this study should inform strategies to manipulate the CaMKK2-signaling axis as a therapeutic approach in cancer.
Authors
Juras, PK; Racioppi, L; Mukherjee, D; Artham, S; Gao, X; Akullian D'Agostino, L; Chang, C-Y; McDonnell, DP
MLA Citation
Juras, Patrick K., et al. “Increased CaMKK2 Expression Is an Adaptive Response That Maintains the Fitness of Tumor-Infiltrating Natural Killer Cells.Cancer Immunol Res, vol. 11, no. 1, Jan. 2023, pp. 109–22. Pubmed, doi:10.1158/2326-6066.CIR-22-0391.
URI
https://scholars.duke.edu/individual/pub1555416
PMID
36301267
Source
pubmed
Published In
Cancer Immunol Res
Volume
11
Published Date
Start Page
109
End Page
122
DOI
10.1158/2326-6066.CIR-22-0391

Eosinophilia in cancer and its regulation by sex hormones.

Gender differences in the functionality of the immune system have been attributed, in part, to direct and indirect effects of sex steroids, especially estrogens, on immune cell repertoire and activity. Notable are studies that have defined roles for estrogens in the regulation of the biology of dendritic cells (DCs), macrophages, T cells and natural killer (NK) cells. Although estrogens can modulate eosinophil function, the mechanisms by which this occurs and how it contributes to the pathobiology of different diseases remains underexplored. Furthermore, although the importance of eosinophils in infection is well established, it remains unclear as to how these innate immune cells, which are present in different tumors, impact the biology of cancer cells and/or response to therapeutics. The observation that eosinophilia influences the efficacy of immune checkpoint blockers (ICBs) is significant considering the role of estrogens as regulators of eosinophil function and recent studies suggesting that response to ICBs is impacted by gender. Thus, in this review, we consider what is known about the roles of estrogen(s) in regulating tissue eosinophilia/eosinophil function and how this influences the pathobiology of breast cancer (in particular). This information provides the context for a discussion of how estrogens/the estrogen receptor (ER) signaling axis can be targeted in eosinophils and how this would be expected to influence the activity of standard-of-care interventions and contemporary immunotherapy regimens in cancer(s).
Authors
MLA Citation
Artham, Sandeep, et al. “Eosinophilia in cancer and its regulation by sex hormones.Trends Endocrinol Metab, vol. 34, no. 1, Jan. 2023, pp. 5–20. Pubmed, doi:10.1016/j.tem.2022.11.002.
URI
https://scholars.duke.edu/individual/pub1557516
PMID
36443206
Source
pubmed
Published In
Trends Endocrinol Metab
Volume
34
Published Date
Start Page
5
End Page
20
DOI
10.1016/j.tem.2022.11.002

Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer.

PURPOSE: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. PATIENTS AND METHODS: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2- advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). RESULTS: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0-7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5-13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. CONCLUSIONS: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2- breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.
Authors
Tsuji, J; Li, T; Grinshpun, A; Coorens, T; Russo, D; Anderson, L; Rees, R; Nardone, A; Patterson, C; Lennon, NJ; Cibulskis, C; Leshchiner, I; Tayob, N; Tolaney, SM; Tung, N; McDonnell, DP; Krop, IE; Winer, EP; Stewart, C; Getz, G; Jeselsohn, R
MLA Citation
Tsuji, Junko, et al. “Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer.Clin Cancer Res, vol. 28, no. 23, Dec. 2022, pp. 5066–78. Pubmed, doi:10.1158/1078-0432.CCR-22-2305.
URI
https://scholars.duke.edu/individual/pub1553665
PMID
36215125
Source
pubmed
Published In
Clinical Cancer Research
Volume
28
Published Date
Start Page
5066
End Page
5078
DOI
10.1158/1078-0432.CCR-22-2305

Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.

Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME) and is refractory to immune checkpoint blockade (ICB). Here, we identify calmodulin-dependent kinase kinase 2 (CaMKK2) as a driver of ICB resistance. CaMKK2 is highly expressed in pro-tumor cells and is associated with worsened survival in patients with GBM. Host CaMKK2, specifically, reduces survival and promotes ICB resistance. Multimodal profiling of the TME reveals that CaMKK2 is associated with several ICB resistance-associated immune phenotypes. CaMKK2 promotes exhaustion in CD8+ T cells and reduces the expansion of effector CD4+ T cells, additionally limiting their tumor penetrance. CaMKK2 also maintains myeloid cells in a disease-associated microglia-like phenotype. Lastly, neuronal CaMKK2 is required for maintaining the ICB resistance-associated myeloid phenotype, is deleterious to survival, and promotes ICB resistance. Our findings reveal CaMKK2 as a contributor to ICB resistance and identify neurons as a driver of immunotherapeutic resistance in GBM.
Authors
Tomaszewski, WH; Waibl-Polania, J; Chakraborty, M; Perera, J; Ratiu, J; Miggelbrink, A; McDonnell, DP; Khasraw, M; Ashley, DM; Fecci, PE; Racioppi, L; Sanchez-Perez, L; Gunn, MD; Sampson, JH
MLA Citation
Tomaszewski, William H., et al. “Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.Nat Commun, vol. 13, no. 1, Oct. 2022, p. 6483. Pubmed, doi:10.1038/s41467-022-34175-y.
URI
https://scholars.duke.edu/individual/pub1555261
PMID
36309495
Source
pubmed
Published In
Nature Communications
Volume
13
Published Date
Start Page
6483
DOI
10.1038/s41467-022-34175-y

Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer.

Despite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes in patients with ovarian cancer. Progress in this regard has been hindered by the lack of relevant syngeneic ovarian cancer models to study tumor immunity and evaluate immunotherapies. To address this problem, we developed a luciferase labeled murine model of high-grade serous ovarian cancer, STOSE.M1 luc. We defined its growth characteristics, immune cell repertoire, and response to anti PD-L1 immunotherapy. As with human ovarian cancer, we demonstrated that this model is poorly sensitive to immune checkpoint modulators. By developing the STOSE.M1 luc model, it will be possible to probe the mechanisms underlying resistance to immunotherapies and evaluate new therapeutic approaches to treat ovarian cancer.
Authors
Russell, S; Lim, F; Peters, PN; Wardell, SE; Whitaker, R; Chang, C-Y; Previs, RA; McDonnell, DP
MLA Citation
Russell, Shonagh, et al. “Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer.Cancers (Basel), vol. 14, no. 17, Aug. 2022. Pubmed, doi:10.3390/cancers14174219.
URI
https://scholars.duke.edu/individual/pub1535321
PMID
36077756
Source
pubmed
Published In
Cancers
Volume
14
Published Date
DOI
10.3390/cancers14174219

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