Donita C. Brady, Ph.D.

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Presidential Professor of Cancer Biology
Department: Cancer Biology

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:
Normal physiology relies on the precise coordination of intrinsic cues, in the form of intracellular kinase signal transduction pathways, with extrinsic cues like nutrient availability to balance cell growth and cell death. Aberrant kinase activation has the capacity to drive oncogenic initiation and progression and thus, small molecule kinase inhibitors have dramatically changed the landscape of cancer treatment. However, the shortcoming of the majority of current kinase inhibitors is the development of resistance, underlining the need to identify new modes of kinase regulation. Since the activity of kinases is governed by a multitude of inputs, such as nutrients, each of the inputs becomes a potential therapeutic vulnerability. Transition metals are unique micronutrients that traditionally function as structural or catalytic cofactors for proteins that are critical for normal physiology and development. Our laboratory uncovered an unexpected link between the cellular acquisition of the metal copper (Cu) and a mitogenic kinase signaling cascade, a discovery that has potential to be leveraged as a new cancer therapy (Turski & Brady et al., Mol Cell Biol, 2012, Brady et al., Nature, 2014, Brady & Crowe et al., Cancer Res, 2017, Xu et al., Clin Cancer Res, 2018). The work in our laboratory has uncovered a critical mechanistic function for Cu as a non-structural intracellular mediator of signaling, which was previously reserved for redox-inactive metals like Zn2+, K+, Na+, and Ca2+ that have well-appreciated roles in cell signaling. However, the molecular mechanisms by which Cu directly cooperates with specific signaling molecules to regulate diverse cellular functions that may contribute to the efficacy of Cu chelators for cancer therapy remain largely undefined. To build on this clinically relevant new paradigm of Cu-mediated kinase signal transduction, our laboratory launched interconnected research focus areas to: i) elucidate the molecular mechanisms and cellular contexts that underlie Cu integration into kinase signaling networks (Kim et al., Metallomics, 2019, Chung, Posimo, Lee, & Tsang et al., PNAS, 2019) and ii) systematically map Cu utilization by oncogenic kinase signal transduction pathways (Tsang & Posimo et al., Nature Cell Biology, 2020). Our mechanistic interrogation of Cu-dependent kinases that are essential for normal cellular processes and are often co-opted and dysregulated in the context of tumorigenesis has expanded the arsenal of targetable vulnerabilities within cancer associated kinase signal transduction pathways. These findings are at the forefront of kinase signaling, cancer biology, and chemical biology and have the potential to be therapeutically exploited as a means to perturb metal availability to essential kinase signaling cascade in tumors.

Lab Members:
Graduate Student:
Caroline Davis, B.S.
Tiffany Tsang, B.A.
Postdoctoral Fellow:
Xingxing Gu, Ph.D.
Yae-Jin Kim, 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
Julianne Davis
Jeffrey Gordon
Danielle Greenberg
Nicole Harrington
Greis Kapexhiu
Calvin Nguyen
Jessica Posimo
Gabriel Rodriguez
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

Blockhuys, S., Brady D.C., & Wittung-Stafshede, P.: Evaluation of copper chaperone ATOX1 as prognostic biomarker in breast cancer. Breast Cancer 27(3): 505-509, May 2020.

Kim, Y.J., Tsang, T., Posimo, J.M, Anderson, G.R., & Brady, D.C.: Inhibition of BCL2 family members increases the efficacy of copper chelation in BRAFV600E-driven melanoma. Cancer Res 80(7): 1387-1400 April 2020.

Tsang, T.*, Posimo, J.M.*, Guidiel, A.A., Cicchini, M., Feldser, D.M., & Brady D.C.: Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. Nat Cell Biol 22(4): 412-424, April 2020 Notes: (* shared first authorship).

Kim, Y.J., Bond, G.J., Tsang, T., Posimo, J.M, Busino, L., & Brady, D.C.: Copper chaperone ATOX1 is required for MAPK signaling and growth in BRAF mutation-positive melanoma. Metallomics 11(8): 1430-1440 August 2019

Rasool, R.U.*, Natesan, R.*, Deng, Q.*, Aras, S., Lal, P., Effron, S.S., Mitchell-Velasquez, E., Posimo, J.M., Carskadon, S., Baca, S.C., Pomerantz, M.M., Siddiqui, J., Schwartz, L.E., Lee, D.J., Palanisamy, N., Narla, G., Den, R.B., Freedman, M.L., Brady, D.C., & Asangani, I.A.: CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation. Cancer Discov 9(11): 1538-1555, November 2019 Notes: (* shared first authorship).

Chung, C.Y.*, Posimo, J.M.*, Lee, S.*, Tsang, T.*, Davis, J.M., Brady, D.C.#, & Chang, C.J.#: Activity-based ratiometric FRET probe reveals oncogene-driven changes in labile copper pools induced by altered glutathione metabolism Proc. Natl. Acad. Sci. U. S. A. 116(37): 18285-18294, September 2019 Notes: (* shared first authorship or # shared corresponding author).

Katona, B.W., Glynn, R.A., Paulosky, K.E., Feng, Z., Davis, C.I., Ma, J., Berry, C.T., Szigety, K.M., Matkar, S., Liu, Y., Wang, H., Wu, Y., He, X., Freedman, B.D., Brady, D.C., & Hua, X: Combined menin and EGFR inhibitors synergize to suppress colorectal cancer via EGFR-independent and calcium-mediated repression of SKP2 transcription. Cancer Res 79(9): 2195-2207 May 2019.

Rivera-Reyes, A., Ye, S., Marino, G., Egolf, S., Ciotti G., Chor S., Liu Y., Posimo, J.M., Park, P.M., Pak, K., Sostre-Colon, J., Tameire, F., Leli, N.M., Koumenis, C., Brady, D.C., Mancuso, A., Weber, K., Gladdy, R., Qi, J., Eisinger-Mathason, T.S.K. : The YAP1-NF-kB axis promotes sarcomagenesis by inactivating circadian clock-mediated unfolded protein responses and autophagy. Cell Death Dis 9(11), October 2018.

Sadeghi R.S., Kulej, K., Kathayat, R.S., Garcia, B.A., Dickinson, B.C., Brady, D.C.#, & Witze, E.S.# : Wnt5a Signaling Induced Phosphorylation Increases Acyl Protein Thioesterase 1 Activity and Promotes Melanoma Metastatic Behavior. Elife April 2018 Notes: (# shared corresponding author).

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 77(22): 6240-6252, Nov 2017 Notes: (* shared first authorship or # shared corresponding author).

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Last updated: 06/30/2020
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