Mammalian models for integrated metabolic and molecular profiling of malignant glioma

项目摘要/摘要 转化性癌症研究需要强大的临床前模型来最有效地研究潜在的 疾病生物学和开发新的治疗方法。虽然所有的模型都是不完美的，但理解 每个模型系统(例如，细胞培养、异种移植)概括特定分子和 人类肿瘤的功能特征。这可能对研究新陈代谢的改变特别相关， 癌症的标志，因为即使是环境的细微变化也会极大地影响 肿瘤。此外，由于癌症新陈代谢受到致癌信号的严格调控，分子的多样性 特定恶性肿瘤内的变化可能会引起独特的代谢特征；这可能会对 代谢途径对肿瘤增殖和生长的依赖性。以最佳方式确定临床前研究的保真度 保留人类癌症代谢特征的模型，这需要对匹配的患者进行交叉比较 具有各种基因改变的肿瘤的组织和临床前模型。然而，这样一个全面的 调查尚未展开。这一提议将表现出一种整合的代谢和分子 匹配的人类肿瘤、患者直接原位异种移植(GliomaPDOX)和细胞的特征 来自胶质母细胞瘤(GBM)患者的线路--这是人类最致命的恶性肿瘤之一，也存在于 独特的大脑新陈代谢环境。在目标1中，稳定同位素标记的代谢示踪和液相色谱- 质谱学(LC-MS)将用于交叉比较预期配对的代谢表型 确定GBM患者肿瘤、GliomaPDOX和细胞系的代谢特征 和/或从患者到临床前模型丢失。目标2建议在基因多样化的临床前确定 GliomaPDOX模型，特定的代谢表型是否与不同的分子特征一致。最后，在 目的3，将进行体内基因敲除实验，以评估测量的代谢 表型代表了GliomaPDOX生长、侵袭和生存的靶向依赖性。总体而言， 本申请中提出的研究将为临床前GBM模型的可译性提供关键的见解 用于研究肿瘤新陈代谢；这最终可能对开发新的 针对GBM的代谢依赖性的治疗，以及潜在的其他恶性肿瘤。

PROJECT SUMMARY/ABSTRACT Translational cancer research requires robust preclinical models to most effectively investigate the underlying biology of disease and develop new therapeutics. While all models are imperfect, it is essential to understand the degree by which each model system (e.g., cell culture, xenograft) recapitulates specific molecular and functional characteristics of human tumors. This may be particularly relevant for studying altered metabolism, a hallmark of cancer, as even subtle changes to the environment can greatly impact the metabolic phenotype of a tumor. Moreover, as cancer metabolism is tightly regulated by oncogenic signaling, the diversity of molecular alterations within a given malignancy may elicit unique metabolic characteristics; which, may greatly influence metabolic pathway dependencies for tumor proliferation and growth. To best determine the fidelity of preclinical models in preserving the metabolic features of human cancer, this requires cross-comparing matched patient tissue and preclinical models across tumors with various genetic alterations. However, such a comprehensive investigation has yet to be undertaken. This proposal will perform an integrated metabolic and molecular characterization of matched human tumors, direct-from-patient orthotopic xenografts (GliomaPDOX), and cell lines from patients with glioblastoma (GBM) – one of the most lethal human malignancies that also reside within the unique brain metabolic milieu. In Aim 1, stable isotope-labeled metabolic tracing and liquid chromatography- mass spectrometry (LC-MS) will be used to cross-compare the metabolic phenotypes of prospectively matched GBM patient tumors, GliomaPDOX, and cell lines to determine the metabolic characteristics that are preserved and/or lost from patient to preclinical model. Aim 2 proposes to determine, in genetically diverse preclinical GliomaPDOX models, whether specific metabolic phenotypes align with distinct molecular signatures. Finally, in Aim 3, in vivo genetic knockdown experiments will be performed to assess whether measured metabolic phenotypes represent targetable dependencies for GliomaPDOX growth, invasion, and survival. Collectively, the studies proposed in this application will provide critical insight into the translatability of preclinical GBM models for studying tumor metabolism; which, may ultimately have important implications for developing new therapeutics against metabolic dependencies in GBM, and potentially, other malignancies.