OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors.
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NAME: Georg Thomas Wondrak
eRA COMMONS USER NAME (credential, e.g., agency login): wondrak
POSITION TITLE: Associate Professor of Pharmacology and Toxicology
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION / DEGREE(if applicable) / Completion Date
MM/YYYY / FIELD OF STUDY /
Swiss Federal Institute of Technology,
Zurich, Switzerland / dipl. Nat. ETH / 05/1987 / Biochemistry
Institute of Biotechnology, Technical University,
Berlin, Germany / Ph.D. / 05/1997 / Biotechnology
A. Personal Statement
My research examines the pathological role of oxidative and proteotoxic stress in solar photodamage and skin cancer (melanoma and nonmelanoma) aiming at the design of novel molecular strategies for prevention and therapeutic intervention. Based on my international professional training and proven track record in skin photodamage-related biochemical and pharmacological research, my research group at the College of Pharmacy and University of Arizona Cancer Center is well positioned to productively interact with Dr. Dickinson to pursue the proposed research that tests feasibility of targeting TLR4 for the photochemoprevention of skin carcinogenesis induced by solar ultraviolet radiation. The project will specifically benefit from our complementary expertise in small molecule therapeutic discovery and cutaneous cancer biology. The following four recent research papers are representative of my ongoing activities in the research area of experimental drug discovery targeting epithelial carcinogenesis:
1. Park, S.L., Justiniano, R., Williams, J.D., Cabello, C.M., Qiao S., and Wondrak,G.T. The tryptophan-derived endogenous arylhydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole (FICZ) is a nanomolar UVA-photosensitizer in epidermal keratinocytes. (2015) J. Invest. Dermatol. 135(6):1649-58.
2. Davis AL,Qiao S,Lesson JL,Rojo de la Vega M,Park SL,Seanez CM,Gokhale V,Cabello CM,and Wondrak GT.Thequinone methide aurin is a heat shock response inducer that causesproteotoxic stress and Noxa-dependentapoptosis in malignant melanomacells. (2015) J Biol Chem. 290 (2): 1623-38.
3. Long M, Tao S, Rojo de la Vega M, Jiang T, Wen Q, Park SL, Zhang DD,and WondrakGT.Nrf2-dependentsuppression of azoxymethane/dextran sulfate sodium-induced coloncarcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. Cancer Prev Res (Phila). 2015 May;8(5):444-54.4.
4. Tao S.,Justiniano, R., Zhang D.D.,and WondrakGT. The Nrf2-inducers tanshinone I and dihydrotanshinone protect humanskin cells and reconstructed human skin against solar simulated UV. (2013) Redox Biol. 1(1):532-41.
B. Positions and Honors
1988 Research Assistant, Centro de Biología Molecular, Universidad Autonoma, Madrid, Spain
1989-1992 Medical Manager, Janssen Pharmaceutica, Neuss, Germany
1993-1997 Research and Teaching Assistant, Ph.D. dissertation ‘Glycation-damage of nucleic acids’,
Institute of Biotechnology, Technical University, Berlin, Germany
1998-2000 Research Postdoctoral Scholar and Scientist III, College of Pharmacy, University of Kentucky
2001-2002 Assistant Research Scientist, College of Pharmacy, University of Arizona
2002-2005 Associate Research Scientist, Department of Pharmacology & Toxicology,
Division of Medicinal Chemistry, College of Pharmacy, University of Arizona
2005-2011 Assistant Professor, Tenure Track, Department of Pharmacology and Toxicology,
Division of Drug Discovery and Development, College of Pharmacy, University of Arizona;
Comprehensive Member, Arizona Cancer Center, Therapeutic Development Program
2008 Annual Sydney E. Salmon Distinguished Investigator award recipient
6/2011-pres. Associate Professor with Tenure, Department of Pharmacology and Toxicology,
College of Pharmacy, University of Arizona
Other Experience
2009-2013 Councilor, American Society for Photobiology (ASP)
2013 reviewer, 'Omnibus R03/R21: Therapeutics', Special Emphasis Panel,
Scientific Review Group 2013/05 ZCA1 RTRB-Z, NIH-NCI
2014 Reviewer, NCI Program Project (P01) Special Emphasis Panel (SEP) III, NIH-NCI
2014 Reviewer, COST (European Cooperation in Science and Technology), Action CM1001
2014 President elect, American Society for Photobiology (ASP)
2015 Editor, ‘Stress Response Pathways in Cancer’, 2015, Springer Biomedical Sciences book
http://www.springer.com/biomed/cancer/book/978-94-017-9420-6
Editorial board membership
(i) Archives of Biochemistry and Biophysics, (ii) Free Radical Research,
(iii) Redox Biology, (iv) Photodermatology, Photoimmunology & Photomedicine
Professional Memberships
Society for Investigative Dermatology
American Society for Photobiology
American Association for Cancer Research
Society of Toxicology
C. Contribution to Science
My NIH-funded laboratory has made a significant scientific impact in the following four core areas of my research:
1. Molecular mechanisms of photo-oxidative stress underlying skin photodamage and carcinogenesis.
My long-term research interest has identified molecular pathways that contribute to skin photooxidative stress (such as endogenous photosensitizer chromophores producing reactive oxygen species upon UVA-photoexcitation) contributing to skin photodamage and UV-photocarcinogenesis. We have recently elucidated a novel pathway of UVA-induced cutaneous proteotoxicity that operates through photo-oxidative inactivation of redox-sensitive, cysteine-dependent cathepsins (CTSB, CTSL) causing autophagic-lysosomal blockade and interference with lysosomal proteolytic clearance of photo-damaged proteins and organelles. In a 2015 research paper, we have successfully identified the most potent endogenous UVA-photosensitizer and aryl hydrocarbon receptor (AhR) agonist ever described in human skin.
a. Park, S.L., Justiniano, R., Williams, J.D., Cabello, C.M., Qiao S., and Wondrak,G.T. The tryptophan-derived endogenous arylhydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole (FICZ) is a nanomolar UVA-photosensitizer in epidermal keratinocytes. (2015) J. Invest. Dermatol. 135(6):1649-58.
b. Williams JD, Bermudez Y, Park SL, Stratton SP, Uchida K, Hurst CA,WondrakGT.Malondialdehyde-derivedepitopes in human skin result from acute exposure to solar UV and occurin nonmelanoma skin cancer tissue. (2014) J Photochem Photobiol B. 5;132:56-65
c. Lamore, S.D., Qiao, S., Horn, D., and Wondrak, G.T. Proteomic Identification of Cathepsin B and Nucleophosmin as Novel UVA-Targets in Human Skin Fibroblasts. (2010) Photochem. Photobiol. 86(6):1307-17. (This publication was featured on the cover of the issue.)
d. Wondrak, G.T., Roberts, M.J., Jacobson, M.K. and Jacobson, E.L. 3-Hydroxypyridine Chromophores are Endogenous Sensitizers of Photooxidative Stress in Human Skin Cells. (2004) J. Biol. Chem. 279, 30009-300020.
2. Novel molecular strategies for tissue protection against environmental insult.
For pharmacological cancer chemoprevention and antioxidant tissue protection from environmental insult, we are aiming at the identification of redox-directed activators of biological stress response pathways. Screening synthetic and food factor-derived compound libraries, we have successfully identified and validated specific small molecule cytoprotectants including inducers of the Nrf2/Keap1-orchestrated antioxidant defense and activators of the HSF1 (heat shock factor 1)-orchestrated heat shock response.
a. Long M, Tao S, Rojo de la Vega M, Jiang T, Wen Q, Park SL, Zhang DD,and WondrakGT.Nrf2-dependentsuppression of azoxymethane/dextran sulfate sodium-induced coloncarcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. Cancer Prev Res (Phila). 2015 May;8(5):444-54.
b. Tao S.,Justiniano, R., Zhang D.D.,and WondrakGT. The Nrf2-inducers tanshinone I and dihydrotanshinone protect humanskin cells and reconstructed human skin against solar simulated UV. (2013) Redox Biol. 1(1):532-41.
c. Wondrak, G.T., Cabello, C.M., Villeneuve, N.F., et al. Cinnamoyl-based Nrf2 Activators targeting Human Skin Cell Photo-oxidative Stress. (2008) Free Radic. Biol. Med. 45(4):385-95.
d. Wondrak, G.T., Jacobson, M.K. and Jacobson, E.L. Identification of Quenchers of Photoexcited States as Novel Agents for Skin Photoprotection. (2005) J. Pharmacol. Exp. Ther., 312, 482-491
3. Redox drug discovery targeting malignant melanoma.
Our recent research suggests that redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through reactive oxygen species represents a specific vulnerability of melanoma cells that can be selectively targeted by apoptogenic redox chemotherapeutics. We are therefore aiming at drug discovery and target identification of small molecule redox modulators displaying anti-melanoma activity in vitro and in vivo:
a. Qiao, S.,Tao, S.,Rojo de la Vega, M.,Park, S.L.,Vonderfecht, A.A.,Jacobs, S.L.,Zhang, D.D.,and Wondrak,G.T. Theantimalarial amodiaquine causes autophagic-lysosomal and proliferativeblockade sensitizing human melanoma cells to starvation- andchemotherapy-induced cell death. (2013) Autophagy 9(12):2087-102.
b. Qiao S, Cabello CM, Lamore SD, Lesson JL,WondrakGT. D-Penicillaminetargets metastatic melanoma cells with induction of the unfoldedprotein response (UPR) and Noxa (PMAIP1)-dependent mitochondrialapoptosis. Apoptosis. 2012 Oct;17(10):1079-94.
c. Cabello, C.M., Lamore, S.D., Bair 3rd, W.B., Qiao, S., Azimian, S., Lesson, J.L., and Wondrak, G.T. The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of Noxa-dependent apoptosis. (2012) Invest. New Drugs 30(4):1289-301.
d. Wondrak G.T. Redox-directed Cancer Therapeutics: Molecular Mechanisms and Opportunities. (2009) Antioxid. Redox Signal. 11(12):3013-3069. [This publication was featured on the cover of the issue; cited by 211 articles as of 6/2015)
4. Novel molecular strategies targeting glycolytic control of melanoma cell survival.
Our previous studies have focused on cellular carbonyl stress modulated by glyoxalase I [lactoylglutathione lyase (EC 4.4.1.5) encoded by GLO1],a ubiquitous cellular defense enzyme involved in the detoxification ofmethylglyoxal (MG), acytotoxic byproduct of glycolysis. We were the first group to demonstrate massive overexpression of GLO1 in malignant melanoma substantiating the hypothesisthat overexpression of GLO1 in metastatic melanoma tissue mayrepresenta crucial survival factor enabling high glycolytic flux(associated with elevated MG production) under hypoxic conditions. We are currently engaged in testing feasibility of undermining glycolytic performance and hypoxic adaptations of malignant melanoma cells by targeting GLO1 using novel structure-based small molecular inhibitors.
a. Bair WB 3rd, Cabello CM, Uchida K, Bause AS, Wondrak G.T. GLO1-Overexpression in human malignant melanoma. (2010) Melanoma. Res. 20(2):85-96.
b. Wondrak, G.T., Jacobson, M.K., and Jacobson, E.L. Anti-Melanoma Activity of Apoptogenic Carbonyl Scavengers. (2006) J. Pharmacol. Exp. Ther. 316:805-814.
c. Wondrak, G.T. Cervantes-Laurean, D., Roberts, M.J., Qasem, J.G., Kim, M., Jacobson, E.L., and Jacobson, M.K. Identification of alpha-dicarbonyl scavengers for cellular protection against carbonyl stress. (2002) Biochem. Pharmacol., 63:381-73.
Complete List of Published Work:
peer reviewed research papers:
http://www.ncbi.nlm.nih.gov/sites/myncbi/georg.wondrak.1/bibliography/40674398/public/?sort=date&direction=ascending
Books:
Editor, ‘Stress Response Pathways in Cancer: From Molecular Targets to Novel Therapeutics’,
2015, Springer [ISBN 978-94-017-9420-6] http://www.springer.com/biomed/cancer/book/978-94-017-9420-
D. Research Support
Ongoing
5P30 CA023074 (Kraft, PI) 03/01/15 - 02/28/16
Arizona Cancer Center – Cancer Center Support Grant
2015 University of Arizona Cancer Center Director’s Challenge Award for Therapeutic Development
Autophagy-directed Anti-melanoma Intervention (Wondrak, PI)
The major goal of this project is to examine feasibility of autophagy-directed antimelanoma intervention using specific cathepsin inhibitors.
Completed
L’OREAL C130820 (Wondrak, PI) 11/01/13 – 10/31/15
L’Oréal Advanced Research $ 100,000 (direct)
Comparative Cutaneous Stress Response Profile of Topical Treatments
The major goal of this project is to perform a comparative cutaneous stress response study of antimycotic topical treatments using organotypic skin models including reconstructed human epidermis.
5R21 CA166926 (Wondrak,Zhang, MPI) 01/01/13 – 12/31/14
NIH/NCI
Targeting Colorectal Carcinogenesis Using a Cinnamon-Derived Food Factor
The goal of this project is to determine the molecular mechanism underlying Nrf2- directed activity of cinnamaldehyde and (II) assess efficacy of cinnamaldehyde as an important food factor targeting colorectal cancer
5R03 CA167580 (Wondrak, PI) 04/01/12 – 03/31/14
NIH/NCI
Testing Feasibility of Artemisinin-based Synthetic-lethal Suppression of Skin Photocarcinogenesis
The goal of this project is to test the feasibility of artemisinin-based suppression of sun light-induced skin cancer in an animal model of the disease, representing a potentially significant advance in the development of novel treatment options suppressing skin cancer.
5R01 CA122484 (Wondrak, PI) 07/01/07 – 05/31/13
NIH/NCI
Targeting Glycolytic Control of Melanoma Cell Survival
This project aims to elucidate the molecular mechanism that regulates melanoma cell survival by methylglyoxal and to test antagonists of methylglyoxal as novel anti-melanoma therapeutics.