Prediction of individualized therapeutic vulnerabilities in cancer from genomic profiles.
Prediction of individualized therapeutic vulnerabilities in cancer from genomic profiles.
复制标题
DOI：
10.1093/bioinformatics/btu164
复制
发表时间：
2014-07-15
期刊：
影响因子：
--
通讯作者：
Sander C
中科院分区：
文献类型：
--
作者：
Aksoy BA;Demir E;Babur Ö;Wang W;Jing X;Schultz N;Sander C
动机：癌症中染色体区域的体细胞纯合缺失，虽然不一定是致癌的，但与正常细胞相比，可能导致癌细胞特异性的治疗脆弱性。最近报道的一个例子是胶质母细胞瘤癌细胞中两种同工酶之一的丢失，使得使用特异性抑制剂选择性地抑制癌细胞的生长，这已经变得完全依赖于第二种同工酶。我们现在已经利用了前所未有的大规模癌症基因组学分析的肿瘤样本在癌症基因组图谱（TCGA）和肿瘤细胞系百科全书中的肿瘤衍生细胞系，以及集成的途径信息系统的可用性，如Pathway Commons，系统地搜索一套全面的上位性脆弱性。结果如下：基于16项TCGA癌症研究和972个癌细胞系中影响代谢酶的纯合缺失，我们在1019个肿瘤样本和482个细胞系中鉴定了4104个候选代谢漏洞。这些漏洞中有高达44%可以用至少一种食品和药物管理局批准的药物来解决。我们建议集中实验来测试这些漏洞，并根据通过临床前过滤器的个性化基因组图谱进行临床试验。我们的结论是，基因组分析将在未来提供一个有前途的基础上，上位脆弱性的网络药理学作为一个有前途的治疗策略。可用性和实施：可在http://cbio.mskcc.org/cancergenomics/statius/沿着补充数据文件中找到一个基于网络的工具，用于探索所有漏洞及其详细信息。联系方式：statius@cbio.mskcc.org补充信息：补充数据可在生物信息学在线获得。
Motivation: Somatic homozygous deletions of chromosomal regions in cancer, while not necessarily oncogenic, may lead to therapeutic vulnerabilities specific to cancer cells compared with normal cells. A recently reported example is the loss of one of the two isoenzymes in glioblastoma cancer cells such that the use of a specific inhibitor selectively inhibited growth of the cancer cells, which had become fully dependent on the second isoenzyme. We have now made use of the unprecedented conjunction of large-scale cancer genomics profiling of tumor samples in The Cancer Genome Atlas (TCGA) and of tumor-derived cell lines in the Cancer Cell Line Encyclopedia, as well as the availability of integrated pathway information systems, such as Pathway Commons, to systematically search for a comprehensive set of such epistatic vulnerabilities. Results: Based on homozygous deletions affecting metabolic enzymes in 16 TCGA cancer studies and 972 cancer cell lines, we identified 4104 candidate metabolic vulnerabilities present in 1019 tumor samples and 482 cell lines. Up to 44% of these vulnerabilities can be targeted with at least one Food and Drug Administration-approved drug. We suggest focused experiments to test these vulnerabilities and clinical trials based on personalized genomic profiles of those that pass preclinical filters. We conclude that genomic profiling will in the future provide a promising basis for network pharmacology of epistatic vulnerabilities as a promising therapeutic strategy. Availability and implementation: A web-based tool for exploring all vulnerabilities and their details is available at http://cbio.mskcc.org/cancergenomics/statius/ along with supplemental data files. Contact: statius@cbio.mskcc.org Supplementary information: Supplementary data are available at Bioinformatics online.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
14.9
作者：
Kanehisa M;Goto S;Sato Y;Furumichi M;Tanabe M
通讯作者：
Tanabe M
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Ho, Allen S.;Kannan, Kasthuri;Roy, David M.;Morris, Luc G. T.;Ganly, Ian;Katabi, Nora;Ramaswami, Deepa;Walsh, Logan A.;Eng, Stephanie;Huse, Jason T.;Zhang, Jianan;Dolgalev, Igor;Huberman, Kety;Heguy, Adriana;Viale, Agnes;Drobnjak, Marija;Leversha, Margaret A.;Rice, Christine E.;Singh, Bhuvanesh;Iyer, N. Gopalakrishna;Leemans, C. Rene;Bloemena, Elisabeth;Ferris, Robert L.;Seethala, Raja R.;Gross, Benjamin E.;Liang, Yupu;Sinha, Rileen;Peng, Luke;Raphael, Benjamin J.;Turcan, Sevin;Gong, Yongxing;Schultz, Nikolaus;Kim, Seungwon;Chiosea, Simion;Shah, Jatin P.;Sander, Chris;Lee, William;Chan, Timothy A.
通讯作者：
Chan, Timothy A.
影响因子：
7
作者：
Kim TM;Xi R;Luquette LJ;Park RW;Johnson MD;Park PJ
通讯作者：
Park PJ