Investigating and targeting metabolic vulnerabilities in chordoma

摘要 作为一名医生兼科学家，我的长期目标是研究驱动癌症的分子机制， 开发改进的治疗方法。脊索瘤是一种罕见的骨肿瘤， 然而，这些治疗方法并不有效，并且脉络膜炎患者面临极高的发病率和复发率。虽然代谢 重编程是癌症的标志，也是肿瘤增殖和存活的关键机制， 了解脉络膜代谢。此外，代谢途径在染色质的形成中起着关键作用 通过调节表观遗传酶的底物可用性，脊索瘤表现出不同的表观基因组 以依赖于转录因子的超级增强子驱动的表达为特征的景观 短尾畸形（TBXT）。同时抑制综合代谢和表观遗传途径的策略提供了一种新的方法， 有前景的治疗选择，并已在多种肿瘤模型中证明有效。脊索瘤对 抑制组蛋白3赖氨酸27（H3 K27）修饰酶赖氨酸脱甲基酶6A和B（KDM 6 A/B）， 其依赖于代谢物α-酮戊二酸（α-KG）。葡萄糖和谷氨酰胺都可以作为前体 到a-KG通过三羧酸（TCA）循环，所以我们假设，无论是抑制代谢 这一途径将抑制增殖并破坏脊索瘤的表观基因组景观。初步研究 证明细胞系模型对谷氨酰胺或葡萄糖的撤回敏感。此外，抑制 产生α-KG的酶异柠檬酸脱氢酶1（IDH 1）导致显著的细胞死亡，增加H3 K27 三甲基化水平降低，以及brachyury表达降低， 因子为了进一步研究葡萄糖和谷氨酰胺代谢在脉络膜炎中的作用，我们将：（1） 表征脉络膜中表观遗传状态的代谢调节，以及（2）评估 抑制α-KG产生作为治疗策略。这项工作将提供深入了解代谢 脊索瘤的网络和表征可操作的代谢脆弱性。重要的是，该项目将 使我能够发展必要的技能，发展成为一个独立的医生，科学家，专注于 了解癌症生物学。

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.