Genetic Polymorphisms Affecting Chemotherapy Disposition

描述(申请人提供)：癌症治疗因个体反应和毒性的不同而变得复杂。负责处理这些药物的酶和转运蛋白的遗传多态可能有助于观察到的可变性。由于这些药物的治疗窗口很窄，在给药前进行药物遗传学筛选可能会导致识别出易发生药物毒性或药物反应不良的特定人群。治疗前基因分型的一个希望是最终允许那些有药物毒性或治疗失败风险的患者得到识别和适当的治疗。药物代谢和靶标酶的遗传异质性已被证明影响几种药物如5-FU、6-MP、阿莫奈德和CPT-11的药代动力学(PK)和毒性的个体间变异性。除了酶，依赖于ATP的effhLx泵，mdr1(Pgp)和MRP2(CMOAT)的遗传变异已经被证明，并导致药物处置的改变。有趣的是，这些等位基因变异中的许多与种族有关，其中许多基因的等位基因频率在高加索人和非裔美国人之间存在显着差异。由于长期以来对临床药理学和不同药物毒性和反应的兴趣，我的职业目标是成为一名临床翻译研究员，具备将药物遗传学的进步与临床试验设计相结合的技能，并最终制定导致剂量优化的研究，在某些情况下为个别患者选择治疗方案。在这项提案中，我描述了一个独特的培训计划，其中包括医学博士Mace Rothenberg在临床研究方面的适当指导和医学博士Richard Kim在基础科学研究方面的指导，在该计划中，药物基因组学领域的基本实验室技术和发现可以应用于精心设计的、假设驱动的临床试验。一个药物遗传技术的教学培训计划被包括在内，为翻译研究的职业生涯提供了坚实的基础。两个翻译研究项目被提议将酶、转运体和核受体的基因多态与临床药代动力学和毒性数据相关联，这些数据来自一组接受化疗药物治疗的癌症患者，这些药物依赖于这些药物处置决定因素的活性。由于这些酶和转运蛋白途径中的许多具有与种族相关的显著变异性，这些项目将侧重于招募高加索和非裔美国人患者，以有效解决这些担忧。范德比尔特-英格拉姆癌症中心和梅哈里医学院之间独特的合作协议将促进这些研究的注册。这笔赠款将使受保护的人有时间进行适当的培训，并有资金支持预期的实验室和学费费用。在完成拟议的培训和项目后，我将在临床转化研究研究的设计和化疗药物处置的基因变异表征方面获得必要的专业知识，以发展以患者为中心的研究的独立职业生涯，并通过R01、R03和R21资助机制有效地竞争未来NIH的支持。

DESCRIPTION (provided by applicant): Cancer treatment is complicated by inter-individual variations in responses and toxicities. Genetic polymorphisms in the enzymes and transporters responsible for the disposition of these drugs may contribute to the observed variability. Due to the narrow therapeutic window of these agents, pharmacogenetic screening prior to anticancer drug administration may lead to identification of specific populations predisposed to drug toxicity or poor drug response. One hope of pre-treatment genotyping would be to eventually allow for those patients who are at risk for drug toxicities or therapeutic failure to be identified and treated appropriately. Genetic heterogeneity in drug metabolizing and target enzymes has been demonstrated to affect the inter-individual variability in the pharmacokineties (PK) and toxicities of several drugs such as 5-FU, 6-MP, amonafide and CPT-11. Besides enzymes, genetic variability in the ATP-dependent effhLx pumps, MDR1 (PGP) and MRP2 (cMOAT), has been demonstrated and results in alterations in drug disposition. Interestingly many of these allelic variations correlate with ethnicity and there are striking differences in the allelic frequencies of many of these genes between Caucasians and African-Americans. Due to a longstanding interest in clinical pharmacology and differential drug toxicity and response, it is my career goal to be a clinical translational researcher with the skills to bridge advances in pharmacogenetics with clinical trial design, and ultimately formulate studies that lead to dose optimization and in some cases treatment selection for individual patients. In this proposal I delineate a unique training plan with appropriate mentorship in clinical research by Mace Rothenberg, MD and mentorship in basic science research by Richard Kim, MD, where basic laboratory techniques and discoveries in the area of pharmacogenomics can be applied in well-designed, hypothesis-driven clinical trials. A plan for didactic training in pharmacogenetic techniques is included to provide a strong foundation for a career in translational research. Two translational research projects are proposed to correlate genetic polymorphisms in enzymes, transporters and nuclear receptors with clinical pharmacokinetic and toxicity data from a cohort of cancer patients treated with chemotherapeutic agents that are dependent upon the activity of these drug disposition determinants. Because a number of these enzyme and transporter pathways have marked variability that correlate with ethnicity, these projects will focus on enrolling Caucasian and African-American patients to effectively address these concerns. Enrollment to these studies will be facilitated by the unique cooperative agreement between the Vanderbilt-Ingram Cancer Center and Meharry Medical College. This grant will allow the protected time to pursue the appropriate training and the funds to support anticipated laboratory and tuition costs. In completing the proposed training and projects, I will gain the necessary expertise in the design of clinical translational research studies and characterization of genetic variations in chemotherapeutic drug disposition to develop an independent career in patient-oriented research and compete effectively for future NIH support, through R01, R03 and R21 funding mechanisms.