Current Challenges and Opportunities in Treating Glioblastoma.
Current Challenges and Opportunities in Treating Glioblastoma.
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DOI：
10.1124/pr.117.014944
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发表时间：
2018-07
影响因子：
21.1
通讯作者：
Neamati N
中科院分区：
文献类型：
--
作者：
Shergalis A;Bankhead A 3rd;Luesakul U;Muangsin N;Neamati N
多形性胶质母细胞瘤(GBM)是最常见和最具侵袭性的原发脑肿瘤，尽管人们努力开发新的治疗方法，但其死亡率仍然很高。GBM表现出肿瘤内和肿瘤间的异质性，有助于耐药和最终的肿瘤复发。对GBM肿瘤的大规模基因组和蛋白质组分析发现了潜在的药物靶点。有效的和“可用药的”靶点必须经过验证，才能启动一场强有力的药物化学运动，最终发现临床候选药物。在这里，我们对GBM药物发现和给药的最新进展进行综述。为了确定GBM药物靶点，我们使用癌症基因组图谱项目的数据进行了广泛的生物信息学分析。我们发现了20个基因：BOC、CLEC4GP1、ELOVL6、ERG、ESR2、FDCSP、Furin、FUT8-AS1、GZMB、IRX3、LITAF、NDEL1、NKX3-1、PODNL1、PTPRN、QSOX1、SEMA4F、TH、VEGFC和C20orf166AS1。重要的是，这些基因中有9个在GBM中的表达高于低级别胶质瘤，可能与疾病的进展有关。在这篇综述中，我们在GBM疾病进展的背景下讨论这些蛋白。我们还在GBM治疗的临床试验中进行了计算多参数优化，以评估小分子的血脑屏障(BBB)通透性。在GBM的背景下给药特别具有挑战性，因为BBB阻碍了小分子的运输。因此，我们讨论了新的药物传递方法，包括纳米粒和前药。鉴于基底膜的侵袭性和以中枢神经系统为靶点的复杂性，有效的治疗方案是一个主要的未得到满足的医疗需求。与GBM疾病进展相关的生物标志物和药物靶点的识别和验证为改进这种毁灭性疾病的治疗提供了一个令人兴奋的机会。
Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and “druggable” targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, and C20orf166AS1 that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.
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影响因子：
2.6
作者：
Banks WA
通讯作者：
Banks WA
影响因子：
3.9
作者：
Akers, Johnny C.;Ramakrishnan, Valya;Kim, Ryan;Phillips, Shirley;Kaimal, Vivek;Mao, Ying;Hua, Wei;Yang, Isaac;Fu, Chia-Chun;Nolan, John;Nakano, Ichiro;Yang, Yuanfan;Beaulieu, Martin;Carter, Bob S.;Chen, Clark C.
通讯作者：
Chen, Clark C.
影响因子：
3.7
作者：
Yan Y;Hong N;Chen T;Li M;Wang T;Guan G;Qiao Y;Chen S;Schartl M;Li CM;Hong Y
通讯作者：
Hong Y
影响因子：
6.6
作者：
Chacko AM;Li C;Pryma DA;Brem S;Coukos G;Muzykantov V
通讯作者：
Muzykantov V
影响因子：
3.5
作者：
Bauerschlag, Dirk O.;Ammerpohl, Ole;Wagner, Wolfgang
通讯作者：
Wagner, Wolfgang