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

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:

ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx. We show that ABL kinases phosphorylate and interact with CUL4A, a cullin ring ligase adaptor, and compete with CPSF1 for CUL4A binding, leading to increased HIF-1α protein levels. Further, we identified the MYC proto-oncogene protein as a second CPSF1 substrate and show that active ABL kinase protects MYC from CPSF1-mediated degradation. These studies uncover a role for CPSF1 in cancer pathobiology as an E3-ligase antagonizing the expression of the oncogenic transcription factors, HIF-1α and MYC.

Authors

Mayro, B; Hoj, JP; Cerda-Smith, CG; Hutchinson, HM; Caminear, MW; Thrash, HL; Winter, PS; Wardell, SE; McDonnell, DP; Wu, C; Wood, KC; Pendergast, AM

MLA Citation

Mayro, Benjamin, et al. “ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.” Proc Natl Acad Sci U S A, vol. 120, no. 16, Apr. 2023, p. e2210418120. Pubmed, doi:10.1073/pnas.2210418120.

URI

https://scholars.duke.edu/individual/pub1571506

PMID

37040401

Source

pubmed

Published In

Proc Natl Acad Sci U S A

Volume

120

Published Date

2023

Start Page

e2210418120

DOI

10.1073/pnas.2210418120

SGC-CAMKK2-1: A Chemical Probe for CAMKK2.

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

Authors

Wells, C; Liang, Y; Pulliam, TL; Lin, C; Awad, D; Eduful, B; O'Byrne, S; Hossain, MA; Catta-Preta, CMC; Ramos, PZ; Gileadi, O; Gileadi, C; Couñago, RM; Stork, B; Langendorf, CG; Nay, K; Oakhill, JS; Mukherjee, D; Racioppi, L; Means, AR; York, B; McDonnell, DP; Scott, JW; Frigo, DE; Drewry, DH

MLA Citation

Wells, Carrow, et al. “SGC-CAMKK2-1: A Chemical Probe for CAMKK2.” Cells, vol. 12, no. 2, Jan. 2023. Pubmed, doi:10.3390/cells12020287.

URI

https://scholars.duke.edu/individual/pub1563637

PMID

36672221

Source

pubmed

Published In

Cells

Volume

Published Date

2023

DOI

10.3390/cells12020287

Molecular Pharmacology of Estrogen and Progesterone Receptors

This chapter provides an update on the mechanisms of action of estrogen and progesterone. Particularly important concepts include nongenomic effects, receptor isoforms that affect agonist/antagonist actions, and the role of coactivators and corepressors in various tissues. The steroid hormones estrogen and progesterone are low-molecular weight, lipophilic hormones that through their action as modulators of distinct signal transduction pathways, are involved in the regulation of reproductive function. These hormones are also important regulators in bone, the cardiovascular system, and the central nervous system. Despite their different roles in these systems, it has become apparent that estrogens and progestins are mechanistically similar. Insights gleaned from the study of each hormone have advanced the understanding of this class of molecules as a whole. Some of the recent mechanistic discoveries that have occurred in the field are highlighted and the subsequent changes in our understanding of the pharmacology of this class of steroid hormones are explored.

Authors

Sherk, AB; McDonnell, DP

MLA Citation

Sherk, A. B., and D. P. McDonnell. “Molecular Pharmacology of Estrogen and Progesterone Receptors.” Treatment of the Postmenopausal Woman: Basic and Clinical Aspects, Third Edition, 2007, pp. 17–28. Scopus, doi:10.1016/B978-012369443-0/50004-1.

URI

https://scholars.duke.edu/individual/pub1567819

Source

scopus

Published Date

2007

Start Page

End Page

DOI

10.1016/B978-012369443-0/50004-1

Estrogens regulate tumor associated tissue eosinophilia to promote tumor growth

Authors

Artham, S; Goyal, A; Byemerwa, J; Chang, C-Y; Mcdonnell, DP

MLA Citation

Artham, Sandeep, et al. “Estrogens regulate tumor associated tissue eosinophilia to promote tumor growth.” Cancer Immunology Research, vol. 10, no. 12, 2022.

URI

https://scholars.duke.edu/individual/pub1564947

Source

wos-lite

Published In

Cancer Immunology Research

Volume

Published Date

2022

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

Published Date

2023

Start Page

109

End Page

122

DOI

10.1158/2326-6066.CIR-22-0391

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