RNAi Analysis and Screening for Study of Genes and Anti-Cancer Treatments

用于基因研究和抗癌治疗的 RNAi 分析和筛选

• 批准号: 7733347
• 负责人: Natasha Caplen
• 金额: $ 39.84万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733347
• 关键词: Antineoplastic Agents; Awareness; Camptothecin; Characteristics; Chemosensitization; Clinical; Complex; Data Set; Development; Dose; Down-Regulation; Drug Interactions; Drug resistance; Exhibits; Future; Gene Expression; Genes; Genetic; Genome; Individual; Investigational Drugs; Molecular Analysis; Molecular Target; Multi-Drug Resistance; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Process; Proteins; RNA Interference; RNA analysis; Reporting; Screening procedure; Technology; Therapeutic Agents; Topoisomerase; Toxic effect; Transcript; Validation; Variant; anti-cancer therapeutic; antitumor agent; asparaginase; base; cancer cell; cancer therapy; cancer type; clinical application; drug development; inhibitor/antagonist; leukemia; pre-clinical; research clinical testing; response; small molecule; therapeutic target

RNAi-based technologies have the potential to enhance many aspects of the anti-cancer drug development process. The increased use of anti-cancer therapeutics targeting specific genetic characteristics (e.g., a fusion transcript or over-expression/amplification of a gene) illustrates the impact molecular analysis has had on the development of anti-tumor agents. Further, there is growing awareness that the genetic background of an individual can influence a patients response to anti-cancer therapeutics. Studies focused on assessing the contribution of genetic and transcriptional variation to a drug response phenotype have become more sophisticated as larger data sets integrating drug-activity with genome-wide DNA/RNA analysis are reported. However, functional approaches to understanding the relationships predicted by these studies have been lacking. We are using RNAi analysis and screening to probe the impact of gene-specific expression on drug-activity, including identification of new proteins that directly or indirectly modulate the pharmacology of anti-cancer therapeutics. We have used the power of RNAi analysis to investigate gene-drug interactions, including study of multi-drug resistance and the activity of the anti-leukemia agent L-Asparaginase. We have also initiated screens that combine RNAi with drug administration. The identification of molecular targets that can act to modulate the activity of anti-cancer drugs has become an important application for RNAi screening approaches. This approach combines RNAi with administration of a small molecule compound or biologic to identify proteins whose down-regulation modulates the activity of a therapeutic agent. This approach has the potential to enhance the clinical application of an established or investigational drug by: (1) identifying synergistic molecular targets that exploit complementary vulnerabilities within a cancer cell, (2) enabling the use of lower concentrations of a drug that exhibits dose-dependent non-specific toxicities, (3) overcoming drug resistance, and, (4) broadening the clinical application of a drug to other cancer types. We began our drug-RNAi screening projects focusing on a chemosensitization (synthetic-lethal) approach using a clinical relevant drug with a defined molecular target and mode of action, the topoisomerase 1 inhibitor camptothecin (CPT), to enable validation of our screens in the context of established drug activity. Future screens will examine drugs with less defined or more complex mechanism of action and/or drugs undergoing pre-clinical or early clinical testing.

基于RNAi的技术有可能增强抗癌药物开发过程的许多方面。针对特定遗传特征的抗癌疗法的使用增加（例如，基因的融合转录本或过表达/扩增）说明了分子分析对抗肿瘤剂的发展的影响。 此外，人们越来越意识到，个体的遗传背景会影响患者对抗癌治疗剂的反应。据报道，随着较大的数据集将药物活性与全基因组DNA/RNA分析相结合，旨在评估遗传和转录变异对药物反应表型的贡献的研究变得更加复杂。但是，缺乏理解这些研究预测的关系的功能方法。我们正在使用RNAi分析和筛选来探测基因特异性表达对药物活性的影响，包括鉴定直接或间接调节抗癌疗法药理学的新蛋白质。我们已经使用RNAi分析的能力研究了基因 - 药物相互作用，包括研究多药耐药性和抗白血病药物L-天冬酰胺酶的活性。我们还启动了将RNAi与药物给药结合的筛选。可以在调节抗癌药物活性的分子靶标的鉴定已成为RNAi筛选方法的重要应用。这种方法将RNAi与施用小分子化合物或生物学结合使用，以鉴定其下调调节治疗剂活性的蛋白质。这种方法具有通过：（1）确定在癌细胞中利用互补脆弱性的协同分子靶标的临床应用的潜力，（2）能够使用较低浓度的药物，表现出剂量依赖性的非特异性毒性的药物（（3）孕育耐药性抗药性，（3）对其他癌症的应用（4）扩展（4）扩展（4）扩展。我们开始使用具有定义的分子靶标和作用方式的临床相关药物，即拓扑异构酶1抑制剂camptothecin（CPT），开始使用临床相关药物进行化学敏化（合成致命）方法，以在既定药物活性的背景下启用我们的筛查验证。未来的筛查将检查具有较少定义或更复杂的作用机理和/或正在接受临床前或早期临床测试的药物的药物。