Donita C. Brady, Ph.D.

faculty photo
Presidential Professor of Cancer Biology
Department: Cancer Biology
Graduate Group Affiliations

Contact information
421 Curie Blvd.
Room 612 BRB II/III
Philadelphia, PA 19104
Office: 215-573-9705
Fax: 215-573-6725
Lab: 215-573-9706
Education:
B.S. (Chemistry)
Radford University, Radford, VA, 2003.
Ph.D. (Pharmacology)
University of North Carolina at Chapel Hill, 2008.
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Description of Research Expertise

Research Interests:
The research interests of our laboratory lie at the intersection of cancer biology, signal transduction, and metal homeostasis.

Keywords:
Cancer Biology, Metal Homeostasis, Signal Transduction, Kinases, Small GTPases, Pharmacologic Interventions, Genetically Engineered Mouse Models

Research Details:
Transition metals are tightly regulated metabolites that function as structural or catalytic cofactors for specific proteins critical to normal physiology and development. Copper (Cu) is an essential transition metal for a diverse array of biological processes. Aberrant Cu excretion and absorption are manifested in the extremely rare genetic diseases Menkes and Wilson, respectively. The study of these diseases helped elucidate the cellular machinery responsible for the proper acquisition, distribution, and utilization of Cu. Recently Cu has been found to modulate signaling cascades and gene expression signatures in the context of normal physiology as well as the pathophysiology of diseases such as cancer.

For example, while investigating pharmacologically accessible signaling pathways downstream of oncogenic RAS, we recently demonstrated that genetic ablation of the high affinity Cu transporter CTR1 responsible for Cu uptake resulted in decreased RAF-MEK-ERK signaling through loss of the interaction between Cu and the kinases MEK1/2. This is the first example demonstrating Cu directly regulates the activity of a mammalian kinase, and hence has opened up a new way to explore how metals interact with signaling pathways. Capitalizing on the dependence of oncogenic mutations in the RAS effector protein BRAF for MEK1/2 activity, a multifaceted approach was used to examine this new signaling mechanism in the context of BRAF mutation-positive cancer. Specifically, we reported that decreasing the levels of CTR1, or introducing mutations in MEK1 that disrupt Cu binding, decreased BRAFV600E-driven signaling and tumorigenesis. Furthermore, Cu chelators used in the treatment of Wilson disease decreased the tumor growth of cells either transformed by BRAFV600E or engineered to be resistant to BRAF inhibition. This novel signaling paradigm provides a concrete intersection between Cu availability and MAPK signaling and led to the initiation of a phase I clinical trial (NCT02068079) to combine a Cu chelator with a BRAF inhibitor for the treatment of BRAF mutation-positive melanoma.

However, the molecular mechanisms by which Cu directly cooperates with specific signaling molecules to govern diverse cellular functions remain largely undefined. As such, there is a great need for a better understanding of precisely how Cu and other metals are integrated into kinase signaling networks during normal homeostasis and cancer. Moreover, these findings highlight the prospect of manipulating Cu regulation as a novel means to target essential kinase signal transduction pathways in cancer via a novel mechanism of regulation. As such, our laboratory will pioneer this new area of research by utilizing a multidisciplinary approach, from in vivo mouse models of cancer, biochemistry, molecular biology, and pharmacologic interventions.

In this regard, we are focusing on three interconnected research areas. Specifically, i) elucidating the molecular mechanisms and cellular contexts that underlie Cu integration into the MAPK pathway, ii) systematically mapping the landscape of sensitivity and resistance to perturbations in Cu availability as a new strategy to target kinase signal transduction in cancer, and iii) applying these findings to other transition metals and signaling networks in cancer.

Lab Members:
Graduate Student:
Caroline Davis, B.S.
Julianne Davis, B.S.
Tiffany Tsang, B.A.
Post Baccalaureate Scholar:
Gabriel Rodriguez
Postdoctoral Fellow:
Jessica Posimo, Ph.D.
Undergraduates:
Gavin Bond
Administrative Coordinator:
Deb Sneddon
dsneddon@mail.med.upenn.edu
215-573-2281
Alumni:
Prince Addai
Farrah Alkahleel
Victoria Belka
Jessica Blanchard
Tiyanna Brown
Danielle Greenberg
Calvin Nguyen
Jaimarie Sostre Colon
Debbie Spivak
Rotation Projects:
Rotation projects are available in each area of interest in the lab. Please contact Dr. Brady for details.

Selected Publications

Brady, D.C., Crowe, M.S. Greenberg, D.N., & Counter, C.M. : Copper chelation inhibits BRAFV600E driven melanomagenesis and counters resistance to BRAFV600E and MEK1/2 inhibitors. Cancer Res In Revision, 2017.

Sammons, S., Brady, D.C., Vahdat, L.T., & Salama, A.K.S. : Copper suppression as a cancer therapy: the rationale for copper chelating agents in BRAFV600 mutated melanoma. Melanoma Manag 3(3): 207-216 Sept 2016.

Chen, H.Y., Brady, D.C., & Villanueva, J.: Double Trouble: Kinase domain duplication as a new path to drug resistance. Pigment Cell and Melanoma Research 29(5): 493-495, Sept 2016.

Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao X, Chaikuad A, Knapp S, Xiao K, Campbell SL, Thiele DJ, Counter CM: Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509(7501): 492-496, May 2014.

Turski ML, Brady DC, Kim HJ, Kim BE, Nose Y, Counter CM, Winge DR, Thiele DJ: A novel role for copper in Ras/mitogen-activated protein kinase signaling. Molecular and Cellular Biology 32(7): 1284-1295, April 2012.

Kashatus DF, Lim KH, Brady DC, Pershing NLK, Cox AD, Counter CM: RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature Cell Biology 13(9): 1108-1115, Sept 2011.

Zipfel PA, Brady DC, Kashatus DF, Ancrile BD, Tyler DS, Counter CM: Ral activation promotes melanomagenesis. Oncogene 29(34): 4859-4864, Aug 2010.

Lim KH, Brady DC, Kashatus DF, Ancrile BB, Der CJ, Cox AD, Counter CM: Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Molecular and Cellular Biology 30(2): 508-523, Jan 2010.

O'Hayer KM, Brady DC, Counter CM: ELR+ CXC chemokines and oncogenic Ras-mediated tumorigenesis. Carcinogenesis 30(11): 1841-1847, Nov 2009.

Madigan JP, Bodemann BO, Brady DC, Dewar BJ, Keller PJ, Leitges M, Philips MR, Ridley AJ, Der CJ, Cox AD: Regulation of Rnd3 localization and function by protein kinase C alpha-mediated phosphorylation. The Biochemical Journal 424(1): 153-161, Nov 2009.

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Last updated: 11/15/2017
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