Population-Specific Genetic Determinants of Susceptibility to Chemotherapies

化疗易感性的人群特异性遗传决定因素

• 批准号: 7673175
• 负责人: Peter Hugh O'Donnell
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673175
• 关键词: Accident and Emergency department; Adverse effects; African; Antineoplastic Agents; Asians; Cancer Patient; Candidate Disease Gene; Carboplatin; Caring; Caucasians; Caucasoid Race; Cisplatin; Clinical; Clinical Trials; Clinical Trials Design; Data; Development; Dose; Drug toxicity; Enrollment; Equilibrium; Ethnic Origin; Event; Experimental Models; Frequencies; Future; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; Genie; Genotype; Hematology; Heterogeneity; Hospitalization; In Vitro; Individual; Investigation; Knowledge; Lead; Learning; Life; Malignant Neoplasms; Metabolism; Minority; Modeling; Modification; Morbidity - disease rate; Operative Surgical Procedures; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Phenotype; Platinum; Platinum Compounds; Population; Pre-Clinical Model; Predisposition; Radiation; Risk; Sampling; Single Nucleotide Polymorphism; Therapeutic Index; Toxic effect; Toxicity due to chemotherapy; Validation; Visit; Work; base; burden of illness; chemotherapy; cytotoxic; cytotoxicity; drug development; experience; genome wide association study; genome-wide; indium arsenide; lymphoblastoid cell line; malignant breast neoplasm; nephrotoxicity; novel; oncology; standard care; trait

DESCRIPTION (provided by applicant): The paradigm of individualized drug therapy based on an individual's unique genetic make-up is especially desirable in the field of hematology/oncology, where the therapeutic index is often narrow, and the consequences of chemotherapy drug toxicity can be life-threatening. If clinicians could better predict which individuals are at the greatest risk of suffering chemotherapy-related toxicities, this could greatly impact the overall care of cancer patients. For cancer drugs, development of toxicities is not universally predictable among all individuals being treated. Evidence suggests that genetic differences between individuals, and between populations, might explain a significant portion of this heterogeneity. For example, Asians have significantly higher rates of platinum chemotherapy-related toxicities compared to other populations. This observation suggests that genetic polymorphisms unique to, or present at higher rates in, Asians might explain this difference. If one could identify "platinum toxicity susceptibility polymorphisms" in populations and individuals, prediction of platinum toxicity risk based on genotype might be possible. Hypothesis: Germline genetic polymorphisms are critical determinants of platinum chemotherapy-related toxicity. We have developed an experimental model employing EBV-transformed B-lymphoblastoid cell lines (LCLs) from healthy individuals of different ethnic backgrounds that permits elucidation of genetic determinants of chemotherapy-related toxicity susceptibility via an unbiased genome-wide approach. In this proposal, we apply this model toward discovery of germline single nucleotide polymorphisms (SNPs) governing toxicity susceptibility to two platinum chemotherapies, cisplatin and carboplatin. We will first identify SNPs which associate with in vitro cytotoxicity in LCLs from Asian individuals, since Asians represent an "enriched toxicity phenotype" population. Then, using SNPs identified in Asians, in conjunction with genotype information from Caucasians and Africans, we will identify SNPs existing "across-populations" which may predict platinum toxicity susceptibility in any individual, regardless of ethnicity. "Cross population" SNPs will then be subjected to validation in our second aim, which establishes a clinical trial enrolling cisplatin-treated patients to determine whether the pre-clinically derived "cisplatin toxicity" SNPs predictably associate with development of cisplatin-related nephrotoxicity. The trial will also permit identification of additional, novel, "cisplatin nephrotoxicity" SNPs through a secondary genome-wide association analysis of patient samples. This information could lead to more judicious use of chemotherapy in cancer patients, potentially allowing chemotherapies to be chosen and/or dosed based on an individual's personal risk of developing side- effects, balanced against the potential benefits. On a population scale, results of this work have the potential to reduce the significant burden of illness that can be conferred by chemotherapy. For the trainee, the proposal represents a comprehensive learning experience in both basic pharmacogenetic discovery and clinical trial design.

描述（由申请人提供）：基于个体独特遗传组成的个体化药物治疗的范例在血液学/肿瘤学领域中是特别期望的，其中治疗指数通常较窄，并且化疗药物毒性的后果可能危及生命。 如果临床医生能够更好地预测哪些人最有可能遭受化疗相关毒性，这可能会极大地影响癌症患者的整体护理。 对于癌症药物，毒性的发展在所有接受治疗的个体中并不是普遍可预测的。 有证据表明，个体之间和种群之间的遗传差异可能解释了这种异质性的重要部分。 例如，与其他人群相比，亚洲人的铂类化疗相关毒性发生率显著较高。 这一观察结果表明，亚洲人特有的或在亚洲人中出现率较高的遗传多态性可能可以解释这种差异。 如果人们能够在人群和个体中识别出“铂毒性易感性多态性”，基于基因型的铂毒性风险预测可能是可能的。 假设：生殖系遗传多态性是铂类化疗相关毒性的关键决定因素。 我们开发了一种实验模型，采用来自不同种族背景的健康个体的EBV转化的B淋巴母细胞系（LCL），该模型允许通过无偏倚的全基因组方法阐明化疗相关毒性易感性的遗传决定因素。 在这个建议中，我们应用这个模型对发现生殖细胞单核苷酸多态性（SNPs）管理毒性敏感性两个铂类化疗，顺铂和卡铂。 我们将首先鉴定与亚洲个体LCL体外细胞毒性相关的SNP，因为亚洲人代表“富集毒性表型”人群。 然后，使用在亚洲人中鉴定的SNP，结合来自高加索人和非洲人的基因型信息，我们将鉴定存在的SNP“跨人群”，其可以预测任何个体的铂毒性易感性，无论种族如何。 然后，在我们的第二个目标中，“交叉群体”SNP将经受验证，该目标建立了招募顺铂治疗患者的临床试验，以确定临床前衍生的“顺铂毒性”SNP是否可预测地与顺铂相关肾毒性的发展相关。 该试验还将允许通过对患者样本进行二次全基因组关联分析来鉴定额外的、新的“顺铂肾毒性”SNP。 该信息可以导致在癌症患者中更明智地使用化疗，潜在地允许基于个体的发展副作用的个人风险来选择和/或给药化疗，与潜在的益处相平衡。 在人口规模上，这项工作的结果有可能减少化疗可能带来的重大疾病负担。 对于受训者来说，该提案代表了基础药物遗传学发现和临床试验设计方面的全面学习经验。