Zolotovskaia Marianna A, Sorokin Maxim I, Emelianova Anna A, Borisov Nikolay M, Kuzmin Denis V, Borger Pieter, Garazha Andrew V, Buzdin Anton A
Oncobox Ltd., Moscow, Russia.
Department of Oncology, Hematology and Radiotherapy of Pediatric Faculty, Pirogov Russian National Research Medical University, Moscow, Russia.
Front Pharmacol. 2019 Jan 23;10:1. doi: 10.3389/fphar.2019.00001. eCollection 2019.
Despite the significant achievements in chemotherapy, cancer remains one of the leading causes of death. Target therapy revolutionized this field, but efficiencies of target drugs show dramatic variation among individual patients. Personalization of target therapies remains, therefore, a challenge in oncology. Here, we proposed molecular pathway-based algorithm for scoring of target drugs using high throughput mutation data to personalize their clinical efficacies. This algorithm was validated on 3,800 exome mutation profiles from The Cancer Genome Atlas (TCGA) project for 128 target drugs. The output values termed Mutational Drug Scores (MDS) showed positive correlation with the published drug efficiencies in clinical trials. We also used MDS approach to simulate all known protein coding genes as the putative drug targets. The model used was built on the basis of 18,273 mutation profiles from COSMIC database for eight cancer types. We found that the MDS algorithm-predicted hits frequently coincide with those already used as targets of the existing cancer drugs, but several novel candidates can be considered promising for further developments. Our results evidence that the MDS is applicable to ranking of anticancer drugs and can be applied for the identification of novel molecular targets.
尽管化疗取得了重大进展，但癌症仍然是主要死因之一。靶向治疗彻底改变了这一领域，但靶向药物的疗效在个体患者之间存在显著差异。因此，靶向治疗的个性化仍然是肿瘤学中的一个挑战。在此，我们提出了基于分子通路的算法，利用高通量突变数据对靶向药物进行评分，以实现其临床疗效的个性化。该算法在来自癌症基因组图谱（TCGA）项目的128种靶向药物的3800个外显子突变谱上得到了验证。输出值称为突变药物评分（MDS），与临床试验中已发表的药物疗效呈正相关。我们还使用MDS方法将所有已知的蛋白质编码基因模拟为假定的药物靶点。所使用的模型是基于来自COSMIC数据库的针对八种癌症类型的18273个突变谱构建的。我们发现，MDS算法预测的命中靶点经常与那些已被用作现有癌症药物靶点的靶点一致，但有几个新的候选靶点有望进一步开发。我们的结果证明，MDS适用于抗癌药物的排名，并可用于识别新的分子靶点。
