Druggable genomic landscapes of high-grade gliomas.
Druggable genomic landscapes of high-grade gliomas.
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高级别胶质瘤的可药物基因组景观。
DOI：
10.3389/fmed.2023.1254955
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发表时间：
2023
影响因子：
3.9
通讯作者：
Anagnostou, Valsamo
中科院分区：
文献类型：
--
作者：
Ghanem, Paola;Fatteh, Maria;Kamson, David Olayinka;Balan, Archana;Chang, Michael;Tao, Jessica;Blakeley, Jaishri;Canzoniero, Jenna;Grossman, Stuart A.;Marrone, Kristen;Schreck, Karisa C.;Anagnostou, Valsamo
关键词：
尽管高级别胶质瘤的基因组前景广阔，但基因组定制靶向治疗的长期生存益处仍然令人沮丧。使用胶质母细胞瘤（GBM）作为高级别胶质瘤的代表性实例，我们评估了来自癌症基因组图谱（TCGA）的388个GBM中热点突变的克隆结构和分布。突变与54种靶向治疗相匹配，然后根据药物在高级别胶质瘤中的临床疗效对药物生化特性进行综合评价。然后，我们评估了约翰霍普金斯分子肿瘤委员会（JH MTB; n = 50）审查的具有靶向突变的高级别胶质瘤患者队列的临床结局。在评估的1，156个序列改变中，28.6%代表热点。虽然GBM中热点突变的频率与具有可操作热点改变的癌症类型相当，但与乳腺癌（4.9%）、肺癌（4.4%）和黑色素瘤（1.4%）相比，GBM具有更高比例的影响热点的亚克隆突变（7.0%）。在研究靶向治疗与复发性改变配对的生物化学特征时，我们发现在具有临床疗效的药物中，GBM细胞系中存在脂溶性较高和IC 50较低的趋势。药物的半衰期、分子量、表面积和与外排转运蛋白的结合与临床疗效无关。在接受靶向治疗的IDH 1野生型高级别胶质瘤患者的JH MTB队列中，曲美替尼单药治疗或与达拉非尼联合治疗使75%携带BRAF或NF 1可操作突变的患者获得放射学部分缓解。卡博替尼在两名携带MET和PDGFRA/KDR扩增的患者中赋予放射学部分应答。接受基因型匹配的靶向治疗的IDH 1野生型胶质瘤患者的无进展生存期（PFS）和总生存期（OS;分别为7.37和14.72）长于未接受靶向治疗的患者（分别为2.83和4.2个月）。虽然多种宿主、肿瘤和药物相关特征可能限制靶向治疗对高级别胶质瘤患者的递送和疗效，但基因型匹配的靶向治疗可带来有利的临床结局。需要进一步的研究来产生更多关于靶向治疗的生物化学特征对高级别胶质瘤临床疗效的影响的数据。
Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging. Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug’s clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50). Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs’ half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively). While multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.
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影响因子：
15.9
作者：
Batchelor, Tracy T.;Gerstner, Elizabeth R.;Supko, Jeffrey G.
通讯作者：
Supko, Jeffrey G.
影响因子：
4.6
作者：
Dalton WB;Forde PM;Kang H;Connolly RM;Stearns V;Gocke CD;Eshleman JR;Axilbund J;Petry D;Geoghegan C;Wolff AC;Loeb DM;Pratilas CA;Meyer CF;Christenson ES;Slater SA;Ensminger J;Parsons HA;Park BH;Lauring J
通讯作者：
Lauring J
影响因子：
5.7
作者：
Kizilbash SH;Gupta SK;Chang K;Kawashima R;Parrish KE;Carlson BL;Bakken KK;Mladek AC;Schroeder MA;Decker PA;Kitange GJ;Shen Y;Feng Y;Protter AA;Elmquist WF;Sarkaria JN
通讯作者：
Sarkaria JN
影响因子：
3.7
作者：
Kelder, J;Grootenhuis, PDJ;Ploemen, JP
通讯作者：
Ploemen, JP
影响因子：
11.5
作者：
Hartmann, Christian;Hentschel, Bettina;Weller, Michael
通讯作者：
Weller, Michael