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

March 01, 2018

End Date

May 31, 2019

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

Awarded By

Department of Defense

Role

Co Investigator

Start Date

March 01, 2017

End Date

February 29, 2020

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

August 20, 2015

End Date

August 19, 2018

Nonclassical signaling of the androgen receptor polyproline domain

Administered By

Pharmacology & Cancer Biology

Awarded By

National Institutes of Health

Role

Co-Mentor

Start Date

July 01, 2009

End Date

June 30, 2010

G Protein Involvement in Oncogenesis and Metastasis

Administered By

Pharmacology & Cancer Biology

Awarded By

National Institutes of Health

Role

Consultant

Start Date

February 01, 2004

End Date

July 31, 2009

Publications:

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

This corrects the article DOI: 10.1038/onc.2016.394.

Authors

Tang, X; Ding, C-K; Wu, J; Sjol, J; Wardell, S; Spasojevic, I; George, D; McDonnell, DP; Hsu, DS; Chang, JT; Chi, J-T

MLA Citation

Tang, X., et al. “Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.” Oncogene, vol. 36, no. 30, July 2017, p. 4379. Pubmed, doi:10.1038/onc.2017.192.

URI

https://scholars.duke.edu/individual/pub1427301

PMID

28604749

Source

pubmed

Published In

Oncogene

Volume

Published Date

2017

Start Page

4379

DOI

10.1038/onc.2017.192

The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor.

The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice although their durability in metastatic disease is limited by activating point mutations within the ligand-binding domain of ESR1 that permit ligand-independent activation of the receptor. It has been suggested that the most commonly occurring ESR1 mutations would likely compromise the clinical activity of selective estrogen receptor downregulators and selective estrogen receptor modulators (SERMs) when used as second-line therapies. It was unclear, however, how these mutations, which are likely coexpressed in cells with ERWT, may impact response to ER ligands in a clinically meaningful manner. To address this issue, we dissected the molecular mechanism(s) underlying ESR1-mutant pharmacology in models relevant to metastatic disease. These studies revealed that the response of ESR1 mutations to ligands was dictated primarily by the relative coexpression of ERWT in cells. Specifically, dysregulated pharmacology was only evident in cells in which the mutants were overexpressed relative to ligand-activated ERWT; a finding that highlights the role of allelism in determining ER-mutant pharmacology. Importantly, we demonstrated that the antagonist activity of the SERM, lasofoxifene, was not impacted by mutant status; a finding that has led to its clinical evaluation as a treatment for patients with advanced ER-positive breast cancer whose tumors harbor ESR1 mutations.

Authors

Andreano, KJ; Baker, JG; Park, S; Safi, R; Artham, S; Oesterreich, S; Jeselsohn, R; Brown, M; Sammons, S; Wardell, SE; Chang, C-Y; Norris, JD; McDonnell, DP

MLA Citation

Andreano, Kaitlyn J., et al. “The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor.” Mol Cancer Ther, vol. 19, no. 7, July 2020, pp. 1395–405. Pubmed, doi:10.1158/1535-7163.MCT-19-1148.

URI

https://scholars.duke.edu/individual/pub1440745

PMID

32381587

Source

pubmed

Published In

Mol Cancer Ther

Volume

Published Date

2020

Start Page

1395

End Page

1405

DOI

10.1158/1535-7163.MCT-19-1148

Impact of CaMKK2 inhibition in tumor-associated myeloid cells on CD8+cytotoxic T-cell recruitment into mammary tumors.

Authors

Mukherjee, D; Baldi, R; Chang, C-Y; Racioppi, L; McDonnell, DP

MLA Citation

Mukherjee, Debarati, et al. “Impact of CaMKK2 inhibition in tumor-associated myeloid cells on CD8+cytotoxic T-cell recruitment into mammary tumors.” Cancer Immunology Research, vol. 8, no. 3, AMER ASSOC CANCER RESEARCH, 2020, pp. 56–57.

URI

https://scholars.duke.edu/individual/pub1434781

Source

wos

Published In

Cancer Immunology Research

Volume

Published Date

2020

Start Page

End Page

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

e14653 Background: Endocrine therapy plus CDK 4/6 inhibition has led to impressive improvements in progression-free survival in patients with advanced, estrogen receptor positive (ER+)/HER2-negative (HER2-) breast cancer. Resistance inevitably emerges, leaving patients with few proven therapeutic options. Our group has recently found that treatment of PIK3CA mutant ER+/HER2- breast cancer with inhibitors of mTORC1/2 and BCL-XL causes impressive synergistic growth suppression and apoptosis induction compared to either agent alone in vitro and in vivo. We sought to assess activity in clinically relevant models of PIK3CA mutant ER+ breast cancer with acquired resistance to endocrine therapy and CDK4/6 inhibition. Methods: Using orthotopic MCF-7 xenograft tumors (ER+/ PIK3CA mutant) that were evolved through serial passaging in vivo to develop tamoxifen resistance (TamR), we developed models of resistant disease. TamR xenograft- bearing mice were then treated for 4-6 weeks with palbociclib (50 mg/kg qd), fulvestrant (100mg/kg qw), or the combination. Mice in each treatment group were divided into two groups following the initial development of resistance, defined by steady growth for 1-2 weeks: one receiving vehicle and the other receiving low dose MLN0128 0.3 mg/kg qd (mTORC1/2 inhibitor) + ABT-737 25 mg/kg qd (BCL-XL /BCL-2 inhibitor). Results: Combination BCL-XL (ABT-737) + mTORC1/2 (MLN0128) inhibition significantly inhibited growth in tamoxifen (p = 0.0045), fulvestrant/tamoxifen (p = 0.0035), palbociclib/tamoxifen (p = 0.0155), and palbociclib/tamoxifen/fulvestrant (0.005) resistant tumors compared to controls. These results were observed without significant animal toxicity, dose-limiting thrombocytopenia secondary to BCL-XL inhibition, or toxicity to normal breast epithelial cells. We have observed tumor regressions in multiple models using doses five- to 12-fold lower than the equivalent doses required to cause clinically meaningful thrombocytopenia in humans and large animal models. Conclusions: Our data establish the rationale for investigating the combination of BCL-XL and mTORC1/2 inhibition in a clinical trial of advanced PIK3CA mutant, ER+/HER2- breast cancer after progression on CDK 4/6 and endocrine therapy. Preclinical work is ongoing with novel inhibitors of BCL-XL.

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

Published Date

2019

Start Page

e14653

End Page

e14653

DOI

10.1200/jco.2019.37.15_suppl.e14653

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

MLA Citation

Wardell, Suzanne E., et al. “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.” Breast Cancer Res Treat, vol. 179, no. 3, Feb. 2020, p. 769. Pubmed, doi:10.1007/s10549-019-05498-0.

URI

https://scholars.duke.edu/individual/pub1421461

PMID

31734822

Source

pubmed

Published In

Breast Cancer Res Treat

Volume

179

Published Date

2020

Start Page

769

DOI

10.1007/s10549-019-05498-0

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

Chair, Department of Pharmacology & Cancer Biology

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