报告题目：From Epigenetic/Metabolic Vulnerabilities to Treatment Opportunities in Triple Negative Breast Cancer
报 告 人：吴芩 博士（加拿大多伦多大学）
Dr. Qin Wu completed her Ph.D. at university of Science and technology under supervision of Dr. Liu Yangzhong. During this period, Dr.Wu joined the lab of Dr. Hidde Ploegh (fellow of National Academy of Sciences) at Whitehead Institute of MIT for biomedical research as a joint graduate student for two years (2013-2015). After graduation in 2015, Dr. Wu moved to University of Toronto and pursued her postdoctoral training with Dr. Cheryl Arrowsmith (fellow of American Association for the advancement of Science) in Canada. There, Dr. Wu trying to explore how to delineate epigenetic and metabolic therapeutic opportunities in triple negative breast cancer. Dr. Wu focuses on precision medicine by integrating cell biology, chemical biology and bioinformatic analysis to identify novel therapeutic targets, and to find biomarker discriminating drug sensitivity. Biomarker searching will be able to help select patient populations that may benefit the most from specific drug treatment. Dr. Wu is also engaged in translating her bench work into clinical trial by developing multiple patient models for drug screening and biomarker validation.
Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 (GLUT1 inhibitor) impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels. In addition, with unbiased combinational chemical probes screening, we discovered crosstalk between glycolytic pathway and histone acetylation and developed effective combination strategies for TNBC therapy.