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

July 01, 1975

End Date

August 31, 2020

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

March 01, 2018

End Date

May 31, 2019

Pharmacological Sciences Training Program

Administered By

Pharmacology & Cancer Biology

Awarded By

National Institutes of Health

Role

Participating Faculty Member

Start Date

July 01, 1975

End Date

August 31, 2020

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

January 01, 2017

End Date

December 31, 2019

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

March 01, 2017

End Date

February 29, 2020

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

2021

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

Published Date

2021

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

Published Date

2021

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

2021

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

Published Date

2021

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

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

Contact:

Profile

https://scholars.duke.edu/person/donald.mcdonnell

Email

donald.mcdonnell@duke.edu

C238a Lev Sci Res Ctr, Durham, NC 27708

Duke Box 3813, Durham, NC 27710