Project Description

Robert Clarke, Ph.D., D.Sc.

Executive Director, The Hormel Institute, UMN
Cancer Systems Biology
Professor of Biochemistry, Molecular Biology and Biophysics, UMN

clarker@umn.edu

Biography

An internationally recognized leader in breast cancer research, Dr. Robert Clarke studies how hormones, growth factors, and other related molecules affect breast cancer, and how breast cancers become resistant to hormonal and cytotoxic chemotherapies. He has broad expertise that includes estrogens, antiestrogens, aromatase inhibitors, cell signaling, bioinformatics, drug resistance, signal transduction, and systems biology.

Having developed a series of hormone resistant breast cancer models that are now widely used in the field, Dr. Clarke continues to develop new experimental models. He is currently developing and applying genomic and novel bioinformatic methods to data from ongoing translational studies in both humans and experimental models of breast cancer. Dr. Clarke and his colleagues have recently identified a new, systems biology-based molecular signaling model in breast cancer that involves several novel oncogenes and suppressor genes. This integrated network incorporates cell stress signaling, protein misfolding (unfolded protein response), and communication among the endoplasmic reticulum, mitochondria, and nucleus of breast cancer cells. Ultimately, this network determines if a breast cancer cell will grow, differentiate or die, and the mechanism by which the cell will die (e.g., apoptosis, ferroptosis, lysosome-dependent cell death, mitochondrial permeability transition-driven necrosis, necroptosis, necrosis, parthanatos, pyroptosis), in response to therapy.

Dr. Clarke leads several multinational molecular medicine studies in breast cancer in collaboration with collaborators at the Mayo Clinic, the University of Edinburgh (Scotland), and Virginia Tech. While at Georgetown University he led an NCI-funded Center for Cancer Systems Biology (2010-2016) and with Dr. Subha Madhavan he led an NCI-funded In Silico Research Center of Excellence (2009-2014). His research is published in over 340 original papers, reviews, and book chapters. Dr. Clarke has edited two books, “Cancer Gene Networks” (co-edited by Dr. Usha Kasid; 2017) and “The Unfolded Protein Response in Cancer” (2019). He also has edited or co-edited several special issues for journals including Breast Cancer Res Treat and Cancer Metastasis Rev. Representative publications from his bibliography can be found elsewhere in this profile.

With extensive experience in peer review, Dr. Clarke served as a member (2010-2014) and as Chair (2011-2013) of the NIH study section Basic Mechanisms of Cancer Therapeutics; previously he had served as Chair of the Basic Science study section for the NIH National Center for Complementary and Alternative Medicine (2002-2008), now the National Center for Complementary and Integrative Health. Dr. Clarke has also chaired multiple study sections for the US Department of Defense Breast Cancer Research Program. He also serves on the editorial boards of over a dozen international peer review journals. For example, Dr. Clarke is a Senior Editor for the journal Cancer Research, an Associate Editor for Endocrine-Related Cancer, and a member of the Editorial Board of over a dozen journals including Clinical Cancer Research and Breast Cancer Research and Treatment.

Dr. Clarke is a Fellow of the American Association for the Advancement of Science in the USA, and a Fellow of the Royal Society of Chemistry, a Fellow of the Royal Society of Medicine, and a Fellow of the Royal Society of Biology in the U.K. An acknowledged teacher and lecturer, he is regularly invited to speak about his research at international and national meetings. Dr. Clarke served as the NCI-Sigma Xi Distinguished Lecturer from 2012-2015.

From 2007-2019, Dr. Clarke served as an Associate Vice President of Georgetown University Medical Center (GUMC) and Director of the Biomedical Graduate Research Organization at GUMC, home to 60% of biomedical research at GUMC. He also served as Dean for Research from 2011-2019 (home to >75% of sponsored research at Georgetown University) and from 2006-2020 as Co-Director of the Breast Cancer Program at the Georgetown Lombardi Comprehensive Cancer Center (first with Dr. Claudine Isaacs and later with Dr. Marc Lippman). Dr. Clarke was as an elected member of the Georgetown University Faculty Senate (2002-2011), serving as Secretary-Treasurer from 2004-2007.

Education

B.Sc.
University of Ulster, Jordanstown, Co. Antrim, Northern Ireland, U.K.
Biological Sciences
M.Sc.
The Queen’s University of Belfast, Belfast, Northern Ireland, U.K.
Biochemistry
Ph.D.
The Queen’s University of Belfast, Belfast, Northern Ireland, U.K.
Biochemistry
Post-doc
National Cancer Institute, National Institutes of Health, Bethesda, MD, U.S.A.
D.Sc.
The Queen’s University of Belfast, Belfast, Northern Ireland, U.K.
Biochemistry

Personal interests and hobbies

Sailing, hiking, biking

Professional memberships

American Association for Cancer Research

Research Interests

Dr. Clarke’s laboratory uses cellular, molecular, and bioinformatic technologies in a systems biology approach to understand the events that affect the sensitivity, or lack thereof, of breast cancers to cytotoxic (chemotherapy) and hormonal therapies (estrogens, antiestrogens, aromatase inhibitors). He has identified a complex signaling network that determines responsiveness to estrogens (e.g., estradiol, estrone, and their sulfates), antiestrogens (e.g., fulvestrant, tamoxifen), and aromatase inhibitors (e.g., letrozole). These studies have implicated several genes expressed in breast cancer specimens from patients and that correlate with clinical outcomes. Mechanistic studies of these genes include interferon regulatory factor-1 (IRF1), nuclear factor kappa B (NFkB), X-box binding protein-1 (XBP1), glucose regulated protein 78 (GRP78), beclin-1 (BECN1), cMYC, eukaryotic initiation factor 2-alpha (eIF2α) and several BCL2 gene family members. Key regulatory events include how cells use the unfolded protein response to endoplasmic reticulum stress to control the balance between cell death, survival and proliferation. Integral to this signaling is the use of autophagy and the altered regulation of several members of the solute carrier (SLC) gene family to fuel intermediate cell metabolism to enable cell survival. This systems-based approach to endocrine responsiveness uses data from multiple omics platforms and tissue microarrays to study prognosis and prediction in breast cancer. A central goal of this work is to determine an individual patient’s prognosis and the likelihood that she will respond to specific therapies. Dr. Clarke’s laboratory also studies tumor dormancy in ER+ breast cancers and the role of cell-cell communication in affecting dormancy and responsiveness to endocrine therapies.

Dr. Clarke has assembled a team of engineers, biostatisticians, computer scientists, and mathematicians to explore the very high dimensional data structures generated in gene expression, metabolomics, and other –omic platforms (Clarke et al., Nature Rev Cancer, 2008). His team includes medical oncologists, pathologists, and cell and molecular biologists in an integrative systems biology approach that involves multiple institutions including The Hormel Institute, Lombardi Comprehensive Cancer Center and other departments at Georgetown University, the Virginia Polytechnic Institute and State University (Virginia Tech), the Mayo Clinic and the University of Edinburgh (Scotland). Initial studies led to the first roadmap for building mathematical models of cell signaling in hormone sensitive and resistant breast cancers (Tyson et al., Nature Rev Cancer, 2011). The emerging network topology captures the integrated nature of the signaling that coordinates several cell functions including proliferation (cell cycle), cell fate (e.g., apoptosis, ferroptosis, necroptosis, parthanatos), and cell metabolism. The models also begin to explain how the unfolded protein response to cell stress integrates signaling to coordinate the cell fate and proliferation decisions in breast cancer cells (Clarke et al., Cancer Res, 2012; Mol Cell Endocrinol, 2015). Integrating transcriptomic and radiomic data has led to a new radiogenomic approach to study breast cancer prognosis (Nature Communications, in press, 2020.)

 

Selected Awards

Fellow, American Association for the Advancement of Science

Publications

Year 2019-22

  1. Sengupta, S. Sevigny, C., Jordan, V.C. & Clarke, R. “Estrogen induced apoptosis in breast cancers is phenocopied by blocking de-phosphorylation of eIF23-alpha protein.” Mol Cancer Res, 17: 918-928, 2019.
  2. Clarke, R., Tyson, J.J., Tan, M., Baumann, W., Xuan, J & Wang, Y. “Systems biology: quantitative multiscale modeling in research in breast and other cancers.” Endocr Relat Cancer, 26: R345-368; doi: 10.1530/ERC-18-0309, 2019.
  3. Pulliam, N., Tang, J. Wang, W., Fang, F., Sood, R. O’Hagan, H.M., Miller, K.D., Clarke, R. & Nephew, K. “Poly-ADP-ribosylation of estrogen receptor-alpha by PARP1 mediates antiestrogen resistance in human breast cancer cells.” Cancers, doi: 10.3390/cancers11010043, 2019.
  4. Yu, W., Zhang, X., Carney, E., Hu, R., Andrade, F., Clarke, R., FitzGerald, K, & Hilakivi-Clarke, L.A. “Effects of jaeumkanghwa-tang on tamoxifen responsiveness in a preclinical ER+ breast cancer model.” Endocr Relat Cancer 26: 339-353, 2019.
  5. Shajahan-Haq, A.N., Demas, D.M., Demo, S., Fallah, Y., Clarke, R., Nephew, K.P., Althouse, S., Sandusky, G. & He, W. “Glutamine metabolism drives growth in advanced hormone receptor positive breast cancer.” Front Oncol, doi: 10.3389/fonc.2019.00686, 2019
  6. Zhang, Y.-W., Nasto, R.E., Jablonski, S.A, Serebriiski, I.G., Surana, R., Murray, J., Johnson, M., Riggins, R.B., Clarke, R., Golemis, E.A. & Weiner, L.M. “RNA interference screening methods to identify proliferation determinants and mechanisms of resistance to immune attack.” Methods Enzymol, 636: 299-322, 2020.
  7. Yu, W., Zhang, X., Carney, E., Hu, R., Andrade, F., Clarke, R., FitzGerald, K, & Hilakivi-Clarke, L.A. “Effects of jaeumkanghwa-tang on tamoxifen responsiveness in a preclinical ER+ breast cancer model.” Endocr Relat Cancer 26: 339-353, 2019.
  8. Shajahan-Haq, A.N., Demas, D.M., Demo, S., Fallah, Y., Clarke, R., Nephew, K.P., Althouse, S., Sandusky, G. & He, W. “Glutamine metabolism drives growth in advanced hormone receptor positive breast cancer.” Front Oncol 9: 686, doi: 10.3389/fonc.2019.00686, 2019
  9. Chen, X., Gu, J., Neuwald, A., Hilakivi-Clarke, L.A., Clarke, R. & Xuan, J. “BICORN: An R package for integrative inference of de novo cis-regulatory modules.” Sci Rep, 10: 7960 (doi: 10.1038/s41598-020-63043-2), 2020.
  10. Chen, L., Wang, N., Herrington, D.M., Clarke, R., Wu, C.-T. & Wang, Y. “debCAM: a Bioconductor R package for fully unsupervised deconvolution of complex tissues.” Bioinformatics, 36: 3927–3929, 2020.
  11. Clarke, R., Kraikivski, P., Jones, B.C., Sevigny, C.M., Sengupta, S. Wang., Y. A systems biology approach to discovering pathway signaling dysregulation in metastasis.” Cancer Metastasis Rev, doi: 10.1007/s10555-020-09921-7, 2020.
  12. Zhang, X., de Oliveira Andrade, F., Zhang, H., Cruz, I., Clarke, R., Gaur, P., Verma, V & Hilakivi-Clarke, L. “Maternal obesity increases offspring’s mammary cancer recurrence and impairs tumor immune response.” Endocr-Relat Cancer, in press, 2020.
  13. Shi, X., Neuwald, A., Wang, X., Wang, T.-L., Hilakivi-Clarke, L.A., Clarke, R. & Xuan, J. “IntAPT: integrated assembly of phenotype-specific transcripts from multiple RNA-seq profiles.” Bioinformatics, in press, 2020
  14. Remoli, A.L., Sgarbanti, M., Perrotti, E., Acchioni, M., Orsatti, R., Acchioni, B., Clarke, R. & Marsili, G. “IĸB kinase-ε-mediated phosphorylation triggers IRF-1 degradation in breast cancer cells.” Neoplasia, 22: 459-469, 2020.
  15. Fan, M., Xia, P., Clarke, R., Wang, Y. & Li, L. “Radiogenomic signatures reveal multiscale intratumour heterogeneity associated with biological functions and survival in breast cancer.” Nature Commun, 11:4861 doi 10.1038/s41467-020-18703-2, 2020.
  16. Chen, X., Neuwald, A.F., Hilakivi-Clarke, L.A., Clarke, R., Wang, T.-L. & Xuan, J. “ChIP-GSM: Inferring active transcription factor modules to predict functional regulatory elements.” PLoS Comput Biol, 2021 https://doi.org/10.1371/journal.pcbi.1009203.
  17. Chen, L., Lu, Y., Wu, C.-T., Clarke, R., Yu, G., Van Eyk, J.E., Herrington, D.E. & Wang, Y. “Data-driven detection of subtype-specific differentially expressed genes.” Sci Rep. 11: 332 doi: 10.1038/s41598-020-79704-1, 2021.
  18. Chen, X., Gu, J., Neuwald, A.F., Hilakivi-Clarke, L.A., Clarke, R. & Xuan, J. “Identifying intracellular signaling modules and exploring pathways associated with breast cancer recurrence.” Sci Rep 11: 385. doi: 10.1038/s41598-020-79603-5, 2021.
  19. Clarke, R., Jones, B.C., Sevigny, C.M., Hilakivi-Clarke, L.A. & Sengupta, S. “Experimental models of endocrine responsive breast cancer: strengths and limitations.” Cancer Drug Resist, 4:762-783, 2021. https://dx.doi.org/10.20517/cdr.2021.33.
  20. Shen, M., Chang, T.-Y., Wu, C.-T., Parjer. S.J., Saylor, G., Wang, Y., yu, G., van Eyk, J., Clarke, R., Herrington, D.M. & Wang, Y. “Comparative assessment and outlook on methods for imputing proteomics data.” Sci Rep, in press, 2022.

More publications can be found here:
https://www.researchgate.net/profile/Robert_Clarke2 and here: https://orcid.org/0000-0002-9278-0854

 

Primary Research Areas:

  • Breast cancer
  • Hormones
  • Growth factors
  • Chemoresistance

 

Research Specialties:

  • Estrogens
  • Antiestrogens
  • Aromatase inhibitors
  • Cell signaling
  • Bioinformatics
  • Drug resistance
  • Signal transduction
  • Systems biology

Professional Affiliations:

American Association for the Advancement of Science (elected Fellow)

American Association for Cancer Research

American Chemical Society

Biochemical Society (U.K.)

Endocrine Society (U.S.A.)

New York Academy of Sciences

Royal Society of Biology (elected Fellow – F.R.S.Biol.)

Royal Society of Chemistry (elected Fellow – F.R.S.Chem.)

Royal Society of Medicine (elected Fellow – F.R.S.Med.)

Sigma Xi

Society for Endocrinology (U.K.)

 

Contact Information