Investigating and targeting metabolic vulnerabilities in chordoma

点击翻译按钮获取中文摘要

ABSTRACT My long-term goal as a physician-scientist is to study the molecular mechanisms that drive cancer in order to develop improved therapeutic approaches. Chordomas are rare bone tumors with no approved medical therapies, and chordoma patients face extremely high morbidity and recurrence rates. While metabolic reprogramming is a hallmark of cancer and key mechanism of tumor proliferation and survival, very little is known about chordoma metabolism. Furthermore, metabolic pathways play a critical role in shaping chromatin through modulation of substrate availability for epigenetic enzymes, and chordomas exhibit distinct epigenomic landscapes characterized by dependency on super-enhancer driven expression of the transcription factor brachyury (TBXT). Strategies to simultaneously inhibit integrated metabolic and epigenetic pathways offer a promising therapeutic option and have proven effective in multiple tumor models. Chordomas respond to inhibition of the histone 3 lysine 27 (H3K27) modifying enzymes lysine demethylase 6A and B (KDM6A/B), which rely on the metabolite alpha-ketoglutarate (a-KG). Both glucose and glutamine can serve as precursors to a-KG through the tricarboxylic acid (TCA) cycle, so we hypothesized that suppression of either metabolic pathway would inhibit proliferation and disrupt the epigenomic landscape of chordomas. Initial studies demonstrate that cell line models are sensitive to withdrawal of glutamine or glucose. Moreover, inhibition of the a-KG-producing enzyme isocitrate dehydrogenase 1 (IDH1) results in marked cell death, increased H3K27 tri-methylation levels, and decreased expression of brachyury, the essential chordoma-specific transcription factor. To investigate further the role of glucose and glutamine metabolism in chordoma, we will: (1) characterize metabolic regulation of the epigenetic state in chordoma, and (2) assess the feasibility of suppressing a-KG production as a therapeutic strategy. This work will provide insight into the metabolic networks of chordomas and characterize actionable metabolic vulnerabilities. Importantly, this project will empower me to develop the necessary skills to develop into an independent physician-scientist focused on understanding cancer biology.