Genetic Polymorphisms Affecting Chemotherapy Disposition

影响化疗倾向的基因多态性

• 批准号: 7753984
• 负责人: ALBERT CRAIG LOCKHART
• 金额: $ 12.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753984
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Accounting; Address; Adopted; Affect; African American; Aftercare; Amonafide; Antineoplastic Agents; Area; Basic Science; Biological Assay; Blood; Camptothecin-11; Cancer Center; Cancer Patient; Caucasians; Caucasoid Race; Chemotherapy-Oncologic Procedure; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Clinical Trials Design; DNA; Data; Doctor of Medicine; Dose; Drug Kinetics; Drug toxicity; Employee Strikes; Enrollment; Enzymes; Ethnic Origin; Failure; Family; Fluorouracil; Foundations; Frequencies; Funding; Funding Mechanisms; Future; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Heterogeneity; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Goals; Grant; Incidence; Individual; Laboratories; Lead; Medical; Mentorship; Metabolism; Myristica fragrans; Nuclear Receptors; Numbers; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Polymerase Chain Reaction; Population; Process; Pump; Research; Research Personnel; Research Project Grants; Risk; Sampling; Screening procedure; Selection for Treatments; Techniques; The Vanderbilt-Ingram Cancer Center at the Vanderbilt University; Therapeutic; Therapy Evaluation; Time; Toxic effect; Training; Translational Research; U-Series Cooperative Agreements; United States National Institutes of Health; Variant; cancer therapy; career; chemotherapeutic agent; chemotherapy; cohort; college; cost; design; drug metabolism; in vivo; insight; interest; multidrug resistance-associated protein 2; patient oriented research; rapid technique; research study; response; skills; training project

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.

描述（由申请人提供）：癌症治疗因反应和毒性的个体间差异而变得复杂。 负责处理这些药物的酶和转运蛋白中的遗传多态性可能有助于观察到的可变性。 由于这些药物的治疗窗口狭窄，抗癌药物给药前的药物遗传学筛查可能会导致鉴定出患有药物毒性或药物反应不佳的特定种群。 预处理基因分型的一种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适当的识别和治疗。 已经证明，药物代谢和靶酶中的遗传异质性会影响药代动力学（PK）的个体间变异性以及几种药物的毒性，例如5-FU，6-MP，Amonafide和CPT-11。 除酶外，已经证明了ATP依赖性EFFHLX泵，MDR1（PGP）和MRP2（CMOAT）的遗传变异性，并导致药物处置的改变。 有趣的是，这些等位基因变化中的许多与种族有关，并且在高加索人和非裔美国人之间，许多这些基因的等位基因频率存在明显的差异。 由于对临床药理学和差异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，其技能具有临床试验设计的临床遗传学技术，并最终提出研究，并在某些情况下为个别患者提供剂量优化的研究。 在这项建议中，我描述了一项独特的培训计划，并在医学博士Richard Kim的MACE Rothenberg，医学博士MACE Rothenberg和基础科学研究中进行了适当的指导。 包括药物遗传学技术教学培训的计划，为转化研究的职业提供了良好的基础。 提出了两个转化研究项目，以将酶，转运蛋白和核受体中的遗传多态性与临床药代动力学和毒性数据相关联，该癌症患者的临床药代动力学和毒性数据与化学治疗剂治疗的癌症患者相关，这些癌症患者依赖于这些药物处置确定性的活性。 由于这些酶和转运蛋白途径中的许多具有与种族相关的可变性，因此这些项目将着重于招募高加索和非裔美国人患者，以有效解决这些问题。 范德比尔特 - 伊吉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入学人数。 这项赠款将使受保护的时间可以进行适当的培训和资金，以支持预期的实验室和学费。 在完成拟议的培训和项目时，我将获得临床翻译研究设计的必要专业知识，并表征化学治疗药物处置中的遗传变异，以通过R01，R03和R21的资金机制在以患者为导向的研究领域发展独立的职业，并有效地争取未来的NIH支持。

项目成果

Organic anion transporting polypeptide 1B3 (OATP1B3) is overexpressed in colorectal tumors and is a predictor of clinical outcome.

• DOI: 10.2147/ceg.s3743
• 发表时间: 2008
• 期刊: Clinical and experimental gastroenterology
• 影响因子: 2.4
• 作者: Lockhart AC;Harris E;Lafleur BJ;Merchant NB;Washington MK;Resnick MB;Yeatman TJ;Lee W
• 通讯作者: Lee W

Overexpression of OATP1B3 confers apoptotic resistance in colon cancer.

• DOI: 10.1158/0008-5472.can-08-1984
• 发表时间: 2008-12-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Lee W;Belkhiri A;Lockhart AC;Merchant N;Glaeser H;Harris EI;Washington MK;Brunt EM;Zaika A;Kim RB;El-Rifai W
• 通讯作者: El-Rifai W

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.

• DOI: 10.1007/s10637-015-0306-7
• 发表时间: 2016-02
• 期刊: Investigational new drugs
• 影响因子: 3.4
• 作者: Amin M;Minton SE;LoRusso PM;Krishnamurthi SS;Pickett CA;Lunceford J;Hille D;Mauro D;Stein MN;Wang-Gillam A;Trull L;Lockhart AC
• 通讯作者: Lockhart AC

A phase I study of cetuximab in combination with gemcitabine and radiation for locally advanced pancreatic cancer.

西妥昔单抗联合吉西他滨和放射治疗局部晚期胰腺癌的 I 期研究。

• 发表时间: 2012
• 期刊: Gastrointestinal cancer research : GCR
• 作者: Chakravarthy,ABapsi;Tsai,ChiaoJillian;O'Brien,Nathan;Lockhart,ACraig;Chan,Emily;Parikh,Alexander;Berlin,JordanD;Merchant,Nipun
• 通讯作者: Merchant,Nipun