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的差异而变得复杂。负责这些药物处置的酶和转运体的遗传多态性可能有助于观察到的变异性。由于这些药物的治疗窗口较窄，在给药前进行药物遗传学筛查可能会导致确定易患药物毒性或药物反应差的特定人群。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的药代动力学（PK）和毒性的个体差异，如5-FU、6-MP、氨酰和CPT-11。除酶外，atp依赖性effhLx泵，MDR1 （PGP）和MRP2 （cMOAT）的遗传变异已被证实，并导致药物处置的改变。有趣的是，这些等位基因中的许多变异都与种族有关，而且在白种人和非裔美国人之间，许多这些基因的等位基因频率存在显著差异。由于对临床药理学和不同药物毒性和反应的长期兴趣，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相结合的技能，并最终制定研究，从而优化剂量，并在某些情况下为个体患者选择治疗方案。在这个建议中，我描述了一个独特的培训计划，由Mace Rothenberg医学博士在临床研究方面提供适当的指导，由Richard Kim医学博士在基础科学研究方面提供指导，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。药物遗传学技术的教学培训计划包括为转译研究的职业生涯提供坚实的基础。我们提出了两个转化研究项目，将酶、转运体和核受体的遗传多态性与一组接受化疗药物治疗的癌症患者的临床药代动力学和毒性数据联系起来，这些药物依赖于这些药物处置决定因素的活性。由于许多这些酶和转运体通路具有与种族相关的显著变异性，因此这些项目将集中于招募白种人和非裔美国人患者以有效地解决这些问题。范德比尔特-英格拉姆癌症中心和梅哈里医学院之间的独特合作协议将促进这些研究的注册。这笔拨款将允许受保护的时间进行适当的培训，并为预期的实验室和学费提供资金支持。在完成拟议的培训和项目后，我将在临床转化研究的设计和化疗药物处置遗传变异的表征方面获得必要的专业知识，从而在面向患者的研究中发展独立的职业生涯，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.