Dr. Elisabeth Martinez received her Ph.D. in Biochemistry and Molecular Biology from Georgetown University where she studied the role of nuclear receptors in transcriptional regulation and went on to do a postdoctoral fellolwship at the National Cancer Institute at NIH. There she worked on

steroid receptors, epigenetics and drug discovery. She joined the faculty at UT Southwestern’sDepartment of Pharmacology where she currently is a tenured Associate Professor. Her scientific program at UT Southwestern is built upon a combined approach of defining the function of

epigenetic enzymes and developing chemical tools to modulate their function. This dual strategy gives her lab the great advantage of simultaneously advancing basic knowledge and generating chemical probes with therapeutic potential. Their main interest is to molecularly define and

pharmacologically target the pathological epigenetic and transcriptional events that characterize cancers and other human diseases, while uncovering new biology. For some years, their research has focused on Jumonji histone demethylase enzymes. Within the context of cancer, her group

has discovered novel roles for Jumonji enzymes in transcriptional adaptation and reprogramming, in the development of chemotherapy resistance, in DNA repair pathways and in the response to radiation therapy in multiple tumor types. These findings have important implications for disease

treatment, opening up new options for overcoming and preventing therapeutic resistance. The small molecule inhibitors they develop have in vivo efficacy without toxicity and have been excellent tools for gaining mechanistic insights into the Jumonji-driven molecular events driving

cancer. In addition to chemical biology and drug discovery, her lab uses genetic, molecular and genomic approaches to understand the underlying biology and catalytic activity of these enzymes.

Abstract: Lysine histone demethylases (KDMs) of the Jumonji family are highly upregulated in multiple solid and hematological malignancies and drive oncogenic gene expression patterns. We have uncovered novel roles of Jumonji KDM enzymes in mediating transcriptional reprogramming

during the development of resistance to chemotherapy and in enhancing DNA repair in response to radiation. We will present data using both genetic and pharmacological approaches to block the activities of Jumonji demethylases in cells and in vivo. Our findings strongly suggest that inhibition

of enzymatic activity is an effective strategy to treat chemoresistant tumors and to prevent the development of drug resistance. Furthermore, we have identified a role for Jumonji enzymes of the Jarid subfamily in DNA repair, by their modulation of H3K4 methylation at sites of DNA

damage. In this context, we will report on the radiosensitizing effects of Jarid inhibition in radiation resistant cancer cells and tumors in vivo. Validation of our findings in human populations will also be presented. Our work opens a new paradigm in our mechanistic understanding of how

histone demethylases mediate drug and radiation resistance and offers a therapeutic strategy to overcome these obstacles.

Elisabeth Martinez, PhD

Assistant Professor

PharmacologyThe Multiple Activities of Jumonji Inhibitor JIB-04

University of Texas Southwestern