Accelerating drug development and repurposing using systematic genetic interactio

利用系统的遗传相互作用加速药物开发和重新利用

• 批准号: 8757890
• 负责人: MICHAEL C BASSIK
• 金额: $ 240.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757890
• 关键词: Address; Biological Markers; Biology; Bioreactors; Cell Culture Techniques; Cell Death Signaling Process; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Disease; Drug Targeting; Elements; FDA approved; Genes; Genetic; Human; Libraries; Malignant Neoplasms; Maps; Measures; Oncogenes; Pharmaceutical Preparations; Pilot Projects; Preclinical Drug Evaluation; Predisposition; Regulation; Specificity; Speed; Stress; Testing; Time; Treatment Protocols; Work; cellular targeting; combat; drug development; drug discovery; functional genomics; genome wide association study; killings; novel; novel therapeutics; public health relevance; response; screening; small hairpin RNA; tool

DESCRIPTION (provided by applicant): Major limitations in drug development are identification of cellular targets (and off-targets) for novel drugs, and discovery of effective drg combinations to combat rapidly evolving diseases such as cancer. Furthermore, drug screens require extensive handling, which limits throughput and increases variability. Finally, genetic background often determines drug susceptibility, complicating selection of optimal treatment regimens. This proposal describes a broad effort in my lab to begin to address these issues by (1) dramatically enhancing the speed, accuracy, and scalability of pooled genome-wide screens using bioreactors to automate cell culture, (2) developing tools to measure pairwise genetic interactions between drug targets in high-throughput, and (3) using these tools to identify synthetic lethal combination targets that are specific to stress and oncogene states. We have shown in pilot studies that our novel high-complexity shRNA libraries (25 shRNAs/gene) can be used to identify the target of a cancer-killing drug with remarkable specificity (Matheny et al., 2013). We have also developed a scalable, rapid strategy to create double-shRNA libraries to simultaneously measure genetic interactions between 100,000's of gene pairs (Bassik et al., 2013). We will adapt this platform to create novel, high-complexity gene modulation libraries composed of shRNA and CRISPR elements targeting pairs of FDA-approved drug targets, and then identify synthetic lethal interactions between these genes in the context of a panel of stresses and oncogenes. Elucidating these synergies will inform our understanding of the underlying biology of stress signaling and cell death regulation, and illuminate new therapeutic combinations using available drugs in diseases such as cancer where these stresses are prevalent. At the same time, the genetic interaction maps will allow us to directly investigate off target effects of drugs, which would streamline the identification of viable candidate molecules for further development. Together, we expect the tools developed here will be broadly useful for functional genomics screening and drug development efforts, and that this work will establish a new paradigm for empirical testing and identification of drug response biomarkers.

描述（由申请人提供）：药物开发的主要局限性是针对新药的细胞靶标（和靶不成目标）的鉴定，以及发现有效的DRG组合来打击快速发展的疾病，例如癌症。此外，药物筛查需要大量的处理，这限制了吞吐量并增加了变异性。最后，遗传背景通常决定药物的敏感性，使最佳治疗方案的选择复杂化。 This proposal describes a broad effort in my lab to begin to address these issues by (1) dramatically enhancing the speed, accuracy, and scalability of pooled genome-wide screens using bioreactors to automate cell culture, (2) developing tools to measure pairwise genetic interactions between drug targets in high-throughput, and (3) using these tools to identify synthetic lethal combination targets that are specific to stress and oncogene states.我们在试点研究中表明，我们的新型高复杂性shRNA文库（25 shRNA/基因）可用于识别具有显着特异性的杀菌剂药物的靶标（Matheny等，2013）。我们还开发了一种可扩展的快速策略，以创建双骨库，以同时测量100,000个基因对之间的遗传相互作用（Bassik等，2013）。我们将适应该平台，以创建由ShRNA和CRISPR元素组成的新型，高复杂性基因调制文库，靶向成对FDA批准的药物靶标，然后在应力和Oncogenes面板中确定这些基因之间的合成致命相互作用。阐明这些协同作用将为我们了解应力信号传导和细胞死亡调节的潜在生物学，并使用可用的药物（例如癌症）阐明新的治疗组合，这些疾病普遍存在。同时，遗传相互作用图将使我们能够直接调查 药物的靶向影响，这将简化可行候选分子以进一步发展的鉴定。我们预计，这里开发的工具将对于功能基因组学筛查和药物开发工作非常有用，并且这项工作将建立一个新的范式，用于对药物反应生物标志物的经验测试和鉴定。

项目成果

E2A-PBX1 Remodels Oncogenic Signaling Networks in B-cell Precursor Acute Lymphoid Leukemia.

• DOI: 10.1158/0008-5472.can-16-1899
• 发表时间: 2016-12-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Duque-Afonso J;Lin CH;Han K;Wei MC;Feng J;Kurzer JH;Schneidawind C;Wong SH;Bassik MC;Cleary ML
• 通讯作者: Cleary ML

Bithionol blocks pathogenicity of bacterial toxins, ricin, and Zika virus.

• DOI: 10.1038/srep34475
• 发表时间: 2016-09-30
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Leonardi W;Zilbermintz L;Cheng LW;Zozaya J;Tran SH;Elliott JH;Polukhina K;Manasherob R;Li A;Chi X;Gharaibeh D;Kenny T;Zamani R;Soloveva V;Haddow AD;Nasar F;Bavari S;Bassik MC;Cohen SN;Levitin A;Martchenko M
• 通讯作者: Martchenko M