Pharmacogenomics of the chemotherapeutic agent paclitaxel

化疗药物紫杉醇的药物基因组学

• 批准号: 8397266
• 负责人: Heather Elizabeth Wheeler
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397266
• 关键词: Adverse effects; Affect; African American; Apoptosis; Breast; Breast Cancer Treatment; Cancer Patient; Cancer and Leukemia Group B; Carboplatin; Cell Line; Cell model; Cells; Clinical; Clinical Research; Clinical Trials; Code; Controlled Environment; Data; Dose; Environmental Risk Factor; Future; Gene Expression; Genes; Genetic; Genetic Markers; Genome; Genotype; Goals; Heritability; Human Genetics; Individual; International; Intervention; Introns; Lead; Malignant neoplasm of lung; Malignant neoplasm of ovary; Measures; Meta-Analysis; Methods; Microtubules; Modeling; Molecular Biology; Neurites; Neuropathy; Nigeria; Non-Small-Cell Lung Carcinoma; Northern Europe; Outcome; Ovarian; Overlapping Genes; Paclitaxel; Patient Care; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physicians; Population; Predisposition; Proteins; Quantitative Trait Loci; Research; Resistance; Risk; Role; Small Interfering RNA; Southwestern United States; Testing; Toxic effect; Treatment Protocols; Treatment outcome; Utah; Variant; Western Europe; Work; alternative treatment; anticancer research; base; chemotherapeutic agent; chemotherapy; cytotoxicity; experience; genetic variant; genome wide association study; genome-wide; improved; interest; lymphoblastoid cell line; malignant breast neoplasm; neoplastic cell; nephrotoxicity; novel; novel marker; patient population; research study; response; sensory neuropathy; statistics; tumor

DESCRIPTION (provided by applicant): The long-term goal of chemotherapeutic pharmacogenomics research is to use genetic information to identify cancer patients at risk of particular drug-induced toxicities and adjust or alter their treatment accordingly. The goal of thi proposal is to discover and functionally validate genetic markers that predict treatment outcomes of the chemotherapeutic agent paclitaxel. Paclitaxel is a microtubule-stabilizing chemotherapy drug often used in the treatment of breast, ovarian and non-small-cell lung cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Common paclitaxel-induced toxicities include peripheral sensory neuropathy and nephrotoxicity, which lead to discontinuation of therapy in approximately 20% of patients. Variation in drug response is likely to be dependent on the combined effects of variation in multiple gene products and environmental factors. By using a classic SNP-based genome-wide association (GWA) approach, the genetics of paclitaxel-induced cytotoxicity has been investigated in lymphoblastoid cell lines (LCLs) under a controlled environment. A preliminary analysis has shown that the top SNPs from a clinical trial of paclitaxel-induced peripheral neuropathy are enriched for SNPs associated with paclitaxel-induced cytotoxicity in LCLs, thus confirming a role for the LCL model in the analysis of genes involved in patient paclitaxel response. An overlap SNP from the preliminary analysis is located in an intron of RFX2. Decreased expression of this gene by siRNA resulted in increased sensitivity of NS-1 cells to paclitaxel measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in paclitaxel sensitivity. Although this approach was successful in identifying an important gene, our plan is to perform gene-based GWA studies because we realize that some of the associated genetic variants may not be detectable using a traditional SNP-based GWA approach. A novel gene-based approach to detect variants of small effect working together that incorporates expression quantitative trait loci (eQTLs), rare and common coding variants, and other functional information will increase power in a gene-level test for association with paclitaxel sensitivity. The fellow and research team also plan to compare the gene-based LCL results to those from clinical studies. Genes that overlap will make excellent candidates to test functionally in cell models of peripheral neuropathy. Additional genes identified in the computational analyses will be tested in the NS-1 model. Thus, in addition to identifying novel markers that contribute to variation in paclitaxel-induced phenotypes, these experiments will enhance understanding of the mechanisms involved in paclitaxel response. This work will provide a framework for choosing SNPs and genes that come from LCL GWA studies to interrogate in future clinical studies. By completing the aims of this proposal, the fellow will gain experience i human genetics and molecular biology while contributing to the field of translational cancer research. PUBLIC HEALTH RELEVANCE: Paclitaxel is a chemotherapy drug often used in the treatment of breast, ovarian and lung cancers, yet variable toxicities among individuals limit successful outcomes. If physicians could predict which patients are more likely to experience these severe side effects, lower doses or alternative treatments could be prescribed. The goal of this research is to discover and validate genetic markers that predict response to paclitaxel in order to improve outcomes for cancer patients.

描述（由申请人提供）：化疗药物基因组学研究的长期目标是利用遗传信息识别具有特定药物诱导毒性风险的癌症患者，并相应地调整或改变其治疗。本提案的目标是发现和功能验证预测化疗药物紫杉醇治疗结果的遗传标记。紫杉醇是一种微管稳定化疗药物，常用于乳腺癌、卵巢癌和非小细胞肺癌的治疗，但个体之间不同的耐药性和毒性限制了成功的结果。常见的紫杉醇引起的毒性包括周围感觉神经病变和肾毒性，这导致大约20%的患者停止治疗。药物反应的变化可能取决于多种基因产物变异和环境因素的综合作用。通过使用经典的基于snp的全基因组关联（GWA）方法，在受控环境下研究了紫杉醇诱导的淋巴母细胞样细胞系（LCLs）细胞毒性的遗传学。初步分析表明，在一项紫杉醇诱导的周围神经病变的临床试验中，顶级snp富含与紫杉醇诱导的LCL细胞毒性相关的snp，从而证实了LCL模型在分析患者紫杉醇反应相关基因中的作用。初步分析的重叠SNP位于RFX2的内含子中。siRNA减少该基因的表达导致NS-1细胞对紫杉醇的敏感性增加，通过减少神经突生长和增加细胞毒性来测量，从功能上证实RFX2参与紫杉醇敏感性。虽然这种方法成功地鉴定了一个重要的基因，但我们的计划是进行基于基因的GWA研究，因为我们意识到一些相关的遗传变异可能无法使用传统的基于snp的GWA方法检测到。结合表达数量性状位点（eqtl）、罕见和常见编码变异以及其他功能信息，一种基于基因的检测小效应变异的新方法将提高与紫杉醇敏感性相关的基因水平检测的能力。该研究员和研究小组还计划将基于基因的LCL结果与临床研究结果进行比较。重叠的基因将成为功能测试的优秀候选者