Genetic Polymorphisms Affecting Chemotherapy Disposition

描述（由申请人提供）：癌症治疗因个体间反应和毒性变化而复杂化。 负责这些药物处置的酶和转运蛋白的遗传多态性可能导致观察到的变异性。 由于这些药物的治疗窗较窄，抗癌药物给药前的药物遗传学筛选可能导致识别易发生药物毒性或药物应答不良的特定人群。 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被识别和适当治疗。 药物代谢和靶酶的遗传异质性已被证明会影响几种药物（如5-FU、6-MP、氨萘非和CPT-11）药代动力学（PK）和毒性的个体间变异性。 除了酶，ATP依赖性effhLx泵，MDR 1（PGP）和MRP 2（cMOAT）的遗传变异性，已被证明，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相关，并且这些基因中的许多等位基因频率在高加索人和非洲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差异药物毒性和反应的兴趣，我的职业目标是成为一名临床转化研究人员，具有将药物遗传学的进步与临床试验设计联系起来的技能，并最终制定导致剂量优化的研究，并在某些情况下为个体患者选择治疗。 在这份提案中，我描绘了一个独特的培训计划，由Mace Rothenberg博士在临床研究中提供适当的指导，并由Richard Kim博士在基础科学研究中提供指导，其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。 在药物遗传学技术的教学培训计划包括在转化研究的职业生涯提供了坚实的基础。 两个转化研究项目提出了相关的酶，转运蛋白和核受体的遗传多态性与临床药代动力学和毒性数据，从一个队列的癌症患者接受化疗药物治疗，这些药物的处置决定因素的活性依赖。 由于这些酶和转运蛋白途径中的一些具有与种族相关的显著变异性，因此这些项目将侧重于招募白人和非洲裔美国人患者，以有效解决这些问题。 Vanderbilt-Ingram癌症中心和Meharry医学院之间的独特合作协议将促进这些研究的注册。 这笔赠款将允许受保护的时间，以追求适当的培训和资金，以支持预期的实验室和学费。 在完成拟议的培训和项目，我将获得必要的专业知识，在临床转化研究研究的设计和化疗药物处置的遗传变异的表征，以发展一个独立的职业生涯在以患者为导向的研究，并有效地竞争未来的NIH支持，通过R 01，R 03和R21资助机制。

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.