Donald P. McDonnell, Ph.D.

Donald P. McDonnell, Ph.D. Glaxo-Wellcome Professor of MCB and Chairman
Department of Pharmacology and Cancer Biology
Professor of Medicine

Duke University School of Medicine
Box 3813
Durham, NC 27710

Phone: 919-684-6035

Research Interests

The nuclear receptor superfamily of ligand-regulated transcription factors are the targets of drugs that account for over 20% of all prescriptions written. Within this family of over 40 proteins are receptors that enable cells to respond to steroid hormones, thyroid hormone, retinoids and vitamin D. Also contained in this family are several "orphan receptors" for which specific hormones remain to be identified. The research in our laboratory is focused on defining the mechanism of action of those nuclear receptors whose expression and/or activity is implicated in the pathogenesis of breast and prostate cancer. We have a specific interest in defining the signaling pathways in these cancers in which the estrogen, progesterone and androgen receptors are engaged. It is anticipated that, by targeting critical steps in the signaling pathways of these receptors, molecules with new mechanisms of action can be developed that are likely to be more effective than existing drugs of this class. Furthermore, we have recently determined that the orphan nuclear receptor, Estrogen Related Receptor-alpha (ERR alpha), is required for the growth and metastasis of breast cancer cells, making it a target of high priority for our group. Projects ongoing in the laboratory range from the most fundamental, where an understanding of the mechanism(s) by which nuclear receptors regulate gene transcription is the goal, to the very applied, where the development of novel pharmaceuticals is the desired endpoint.

Representative Publications

Frigo, D.E., Howe, M.K., Wittmann, B.M., Brunner, A.M., Cushman, I., Wang, Q., Brown, M., Means, A.R. and McDonnell, D.P. (2011) CaM kinase kinase b-mediated activation of the growth regulatory kinase AMPK is required for androgen-dependent migration of prostate cancer cells.  Cancer Res. 71: 528-537.  PMCID: PMC3074523

Chang, C.-Y., Kazmin, D., Kunder, R., Zuercher, W.J. and McDonnell, D.P. (2011) The metabolic regulator ERRa, a downstream target of HER2/IGF-1, as a therapeutic target in breast cancer.  Cancer Cell 20: 500-510.  PMCID: PMC3199323

Nelson, E.R., DuSell, C.D., Wang, X., Howe, M., Evans, G., Michalek, R.D., Rathmell, J.C., Khosla, S., Gesty-Palmer, D. and McDonnell, D.P. (2011) The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors.  Endocrinology 152: 4691-4705.  PMCID: PMC3230052

Wardell, S.E., Nelson, E.R., Chao, C.A. and McDonnell, D.P. (2013) Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: Implications for treatment of advanced disease. Clin. Cancer Res. 19: 2420-2431.  PMCID: PMC3643989

Nelson, E.R., Wardell, S.E., Jasper, J.S., Park, S., Suchindran, S., Howe, M.K., Carver, N.J., Pillai, R.V., Sullivan, P.M., Sondhi, V., Umetani, M., Geradts, J. and McDonnell, D.P. (2013) 27-hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342: 1094-1098.  PMCID: PMC3899689

Safi, R., Nelson, E.R., Chitneni, S.K., Franz, K.J., George, D.J., Zalutsky, M.R. and McDonnell, D.P. (2014) Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 74: 5819-5831. PMCID: PMC4203427

McDonnell, D.P., Park, S., Goulet, M.T., Jasper, J., Wardell, S.E., Chang, C.Y., Norris, J.D., Guyton, J.R. and Nelson, E.R. (2014) Obesity, cholesterol metabolism and breast cancer pathogenesis. Cancer Res. 74: 4976-4982.  PMCID: PMC4167494

Wright, T.M., Wardell, S.E., Jasper, J.E., Stice, J.P., Safi, R., Nelson, E.R. and McDonnell, D.P. (2014) Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Molecular Cancer Research 12: 1829-1839. PMCID: PMC4272635

McDonnell, D.P., Wardell, S.E., Norris, J.D. (2015) Oral selective estrogen receptor downregulators (SERDs), a breakthrough endocrine therapy for breast cancer. J. Med. Chem. 58:4883-4887. PMID: 26039356

Wardell, S.E., Ellis, M.J., Alley, H.A., Eisele, K., VanArsdale, T., Dann, S.G., Arndt, K.T., Primeau, T., Griffin, E., Shao, J., Crowder, R., Lai, J.-P., Norris, J.D., McDonnell, D.P. and Li, S. (2015) Efficacy of SERM/SERD hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin. Cancer Res. 21: 5121-5130. PMID: 25991817