Medium-chain acyl-coenzyme A dehydrogenase as an essential feeder of glioblastoma multiforme

总结 胶质母细胞瘤（GBM）是最致命的人类癌症之一，中位生存期为15至19个月。超过 90%接受当前标准治疗、伴随替莫唑胺和放疗的患者显示， 治疗期间的肿瘤进展。因此，复发是不可避免的，最佳管理是重新评估。 电源不清楚。迫切需要制定改善GBM治疗方案的策略。gbm是 其中最全面的基因组特征的肿瘤，这已证实广泛的间， 肿瘤异质性这些研究已经确定了遗传性病变，为靶向治疗提供了依据- 但迄今为止，GBM的累积遗传特征未能显著影响临床 实践和患者结果。此外，广泛的瘤内异质性GBM被记录为熊 功能相关性，影响对治疗的反应。这包括各种代谢适应， 记录在GBM中。GBM对代谢程序改变的明显依赖性和不断发展的- 癌症中代谢功能异质性和适应性的存在促使对基因进行无偏筛选， 在GBM中提供必需代谢途径的产品。这鉴定了中链酰基辅酶A脱氢酶- ase（MCAD）作为GBM的候选饲养者。本研究的长期目标是确定新的治疗靶点 用于治疗GBM。总体目标是评价GBM中MCAD的致癌机制， 确定这种依赖性是否代表一种治疗机会，要么直接通过靶向治疗， MCAD的作用，或间接通过靶向它调节的癌症相关途径。核心假设是， MCAD在GBM中的基本活性影响脂质代谢、能量产生和/或表观遗传生殖， 语法关注MCAD的理由是基于ACADM和其他酰基- 来自筛选的CoA转移酶，其独特地采用低传代、患者来源的胶质瘤球 （GSCs）在体内询问靶向330个代谢基因的shRNA文库，在体外和体内令人信服 验证GBM模型对MCAD的依赖性，以及MCAD表达升高的频率非常高 在人类疾病中。具体目的是（i）阐明MCAD的作用机制，（ii）评价 MCAD对细胞表观遗传重编程的影响，以及（iii）评估急性MCAD的肿瘤影响和耐受性 表情这项补助金意义重大，因为对癌症基本机制的深刻理解， GBM中的MCAD可能阐明了一种新的分子或靶向途径，可改善患者的结局。 这种致命的疾病。预计如果确定，该研究可能具有很高的翻译相关性 MCAD靶向作用可能与干扰DNA的标准治疗和/或靶向治疗协同作用， 修复.这项研究是创新的，因为靶向脂质降解酶代表了一种新的方法， 一种潜在的癌症治疗剂

Summary Glioblastoma (GBM) is among the deadliest human cancers with a median survival of 15 to 19 months. Over 90% of patients treated with the current standard of care, concomitant temozolomide and radiotherapy, show tumor progression while on treatment. Consequently, recurrence is inevitable and the optimal management re- mains unclear. There is an urgent need to develop strategies for improving treatment options for GBM. GBM is among the most comprehensively genomically characterized tumors, which has confirmed extensive inter- tumoral heterogeneity. These studies have identified genetic lesions that provide a rationale for targeted treat- ments, but to date, the accumulated genetic characterization of GBMs has failed to significantly impact clinical practice and patient outcomes. In addition, extensive intratumoral heterogeneity in GBM is documented as bears functional relevance, influencing response to therapy. This includes varied metabolic adaptations that have been documented in GBM. The clear dependency of GBM on altered metabolic programs and an evolving under- standing of metabolic functional heterogeneity and adaptation in cancer prompted an unbiased screen for gene products that feed essential metabolic pathways in GBM. This identified Medium-chain Acyl-CoA Dehydrogen- ase (MCAD) as candidate feeder of GBM. The long-term goal of this research is identify novel therapeutic targets for the treatment of GBM. The overall objective is to evaluate the oncogenic mechanism of MCAD in GBM to determine whether this dependency represents a therapeutic opportunity, either directly through targeted inhibi- tion of MCAD, or indirectly by targeting the cancer-relevant pathways it regulates. The central hypothesis is that the essential activities of MCAD in GBM influence lipid metabolism, energy production, and/or epigenetic repro- gramming. The rationale for focusing on MCAD is based on the strong emergence of ACADM and other acyl- CoA dehydrogenases from the screening that uniquely employed low-passage, patient-derived glioma spheres (GSCs) in vivo to interrogate an shRNA library targeting 330 metabolism genes, convincing in vitro and in vivo validation of the dependence of GBM models on MCAD, and a very high frequency of elevated MCAD expression in human disease. The specific aims are to (i) elucidate the MCAD mechanism of action, (ii) evaluate the effect of MCAD on epigenetic reprogramming of cells, and (iii) evaluate tumor impact and tolerability of acute MCAD expression. This grant is significant because a deep understanding of the cancer-essential mechanism(s) of MCAD in GBM may illuminate a new molecule or pathway to target that may improve outcomes for patients with this deadly disease. It is anticipated that the research may be of high translational relevance if it is determined that effects of MCAD targeting may synergize with standard-of-care and/or targeted therapies that perturb DNA repair. The research is innovative because targeting lipid degradation enzymes represents a novel approach for a potential cancer therapeutic.