Redox Drug Discovery Targeting Skin Cancer and Solar Photodamage
My drug discovery research program examines the pathological role of oxidative and proteotoxic stress in skin carcinogenesis and solar photodamage. The following synergistic research projects are currently pursued in the Wondrak laboratory:
I. Stress Response Pathways in Cancer
Molecular Mechanisms and Therapeutic Opportunities It is now established that the interplay between environmental exposure and molecular stress response pathways plays a critical role in skin health and disease. Likewise, dysregulated cell stress response pathways play a critical role in tumorigenesis, and a refined mechanistic understanding of this phenomenon at the molecular level promises to open new avenues for targeted therapeutic strategies that may benefit patients in the near future. The following books focusing on the role of genotoxic, proteotoxic, oxidative, metabolic, and inflammatory stress in health and tumorigenesis have been published:
1.'Stress Response Pathways in Cancer’, 2015, Springer [ISBN 978-94-017-9420-6] http://www.springer.com/biomed/cancer/book/978-94-017-9420-6
2.‘Skin Stress Response Pathways: Environmental Factors and Molecular Opportunities’, 2016, Springer [ISBN 978-3-319-43157-4] http://www.springer.com/us/book/9783319431550
II. 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.
III. SPA-Inducers for Photo-Chemoprevention of Skin Cancer and Solar Photodamage
For skin photoprotection and improved photo-chemoprevention we are aiming at the design of pharmacological activators of the innate skin photo-adaptive response (SPA) that antagonizes cutaneous damage from environmental UV exposure. Non-cytotoxic small molecule SPA-inducers, acting through Nrf2-activation and heat shock response upregulation, represent a novel class of topical agents targeting skin photo-oxidative stress.
IV. Targeting the Redox Achilles Heel of 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 prooxidant modulators including genotype-directed quinones and synthetically-lethal endoperoxides displaying anti-melanoma activity in vitro and in vivo.
V. 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 22.214.171.124) encoded by GLO1], a ubiquitous cellular defense enzyme involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis. We were the first group to demonstrate massive overexpression of GLO1 in malignant melanoma substantiating the hypothesis that overexpression of GLO1 in metastatic melanoma tissue may represent an indispensable 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.
VI. Molecular Strategies for Improved Cancer Chemoprevention: Focus on Cinnamon
For cancer chemoprevention and antioxidant protection from environmental insult, we are aiming at the discovery and design of redox-directed activators of biological stress response pathways, a project pursued in close collaboration with Dr. Donna Zhang, College of Pharmacy. Screening synthetic and food factor-derived compound libraries, we engage in the identification of 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 in epithelial cells. We are particularly interested in the chemopreventive development of cytoprotective biofactors derived from cinnamon (cinnamaldehyde) and edible plants of the American Southwest (e.g. betalain-pigments from prickly pear and saguaro fruits).
Dipl. Nat, ETH, Biochemistry, Swiss Federal Institute of Technology Zurich (Switzerland), 1987
PhD, Biotechnology, Technical University of Berlin (Germany), 1997