Clinical Pharmacogenetics

临床药物遗传学

• 批准号: 10702382
• 负责人: William Douglas Figg
• 金额: $ 87.87万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702382
• 关键词: 3' Untranslated Regions; ABCB1 gene; ABCG2 gene; Affect; African; African American; African American population; Alleles; Anaplastic astrocytoma; Anti-Retroviral Agents; Antiepileptic Agents; Antimetabolites; Antineoplastic Agents; Azathioprine; Biological; CYP1A2 gene; CYP1B1 gene; CYP2C19 gene; CYP2D6 gene; CYP3A4 gene; CYP3A5 gene; Candidate Disease Gene; Carboplatin; Case Study; Chemotherapy-Oncologic Procedure; Clinical; Clinical Trials; Code; Colon Carcinoma; Colorectal; Data; Development; Differentiation Antigens; Disease; Dose; Drug Kinetics; Drug Targeting; Drug Transport; Enzymes; Etiology; Fluorouracil; Future; Gender; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Glioblastoma; Goals; HLA Antigens; Hypophosphatemia; Immunoglobulins; Immunosuppressive Agents; Inherited; Investigation; Killer Cells; Knowledge; Laboratories; Link; Malignant Neoplasms; Mediating; Membrane; Metabolism; Minor; Molecular; Movement; Mutation; Nucleotides; Oncology; Organ; Outcome; Paclitaxel; Pancytopenia; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phase I Clinical Trials; Phenotype; Physiology; Plasma; Platinum; Plicamycin; Population; Prior Therapy; Process; Publishing; Recurrence; Refractory; Research; Research Design; Scanning; Statistical Data Interpretation; Therapeutic; Therapeutic Index; Tissues; Topoisomerase Inhibitors; Toxic effect; Transitional Cell Carcinoma; UGT1A1 gene; United States National Institutes of Health; Update; Variant; Vascular Endothelial Growth Factors; Work; Xenobiotics; abiraterone; antiangiogenesis therapy; base; bevacizumab; cancer therapy; chemotherapy; clinical center; clinical effect; cohort; comorbidity; docetaxel; drug development; drug disposition; drug metabolism; experience; experimental study; fluoropyrimidine; genetic association; genetic variant; genotyped patients; improved; inter-individual variation; interest; lenalidomide; metabolic rate; novel; patient response; patient stratification; pharmacodynamic biomarker; phase 1 study; phase II trial; precision medicine; predicting response; programs; racial population; receptor; response; side effect; success; temozolomide; therapeutic protein; therapy outcome; treatment response

Our laboratory has a strong interest in clinical pharmacogenetics. We have integrated pharmacogenetics and pharmacogenomics (PG) research in our drug development efforts to evaluate the impact of genetic variants on drug metabolism, pharmacokinetics (PK), response and toxicity as well as to understand the contribution of inter-individual variation in clinical outcomes in therapies with an already narrow therapeutic window. Given the importance of pharmacogenomics in precision medicine, we are actively involved with implementing the pharmacogenomics program at the NIH Clinical Center. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein, MDR1), ABCG2 (BCRP), SLCO1B3 (OATP1B3, OATP8), CYP3A4, CYP3A5, CYP1B1, CYP2C19, CYP2D6, UGT1A1, UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug PK, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable inter-individual variation in physiology and pharmacotherapy. Thus, we are interested in studying how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome, and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. While many studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability, we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. In the past, we have genotyped patients with the Drug Metabolizing Enzymes and Transporters (DMET) platform (which ascertains 1931 genotypes in 235 genes) to explore potential links between these genes and outcomes from several cancer therapies. In the current fiscal year, we have transitioned over to the updated Pharmacoscan platform, which interrogates 4627 variants in 1191 ADME genes. It also detects 4389 ancestry informative markers, 239 gender markers, 7116 human leukocyte antigen markers, and 1484 killer cell immunoglobulin-like receptor markers. We have studied the PG assessments of many anticancer agents including recently mithramycin, belinostat, docetaxel/lenalidomide/bevacizumab combination, olaparib/carboplatin combination, carfilzomib, azathioprine, abiraterone, and paclitaxel. In a phase II trial of cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma, we found that VEGF genotypes (1498CT and. 634CG) were associated with hypophosphatemia - one of the common grade 3-4 toxicities of cabozantinib in the study. We recently conducted a pharmacogenetic analysis in patients on a recent phase I clinical trial to investigate zotiraciclib combined with temozolomide in recurrent glioblastoma and anaplastic astrocytoma. Zotiraciclib is metabolized by CYP1A2 and CYP3A4; from the pharmacoscan results, we identified a single-nucleotide change in gene coding CYP1A2 (CYP1A2 5347TC; rs2470890). This SNP is also associated with a significant difference in zotiraciclib pharmacokinetics (higher AUCinf value) in a cohort of 13 patients. This PK/PG analysis identified a polymorphism that potentially alters the PK of zotiraciclib, suggesting further investigations are warranted for a genotype-guided dosing to reduce the toxicities. Cancers of the colon are commonly treated with fluoropyrimidines, which often cause severe toxicities in patients with certain variants in DPYD. Moderate to strong evidence indicates that ten genetic variants in DPYD are associated with a reduction in the rate of fluoropyrimidine metabolism, and at least 17 other DPYD genotypes may reduce DPYD function. Several of these variants are observed in specific racial populations, and understanding of genetic variability in specific racial populations will be crucial for future reductions in fluoropyrimidine toxicity. We present a case report of an African-American patient who underwent FOLFOX therapy for a colorectal malignancy who developed profound pancytopenia during treatment. Pharmacoscan analysis identified the patient with the DPYD Y186C variant (rs115232898), an uncommon allele (minor allele frequency (MAF) = 0.032 in African-Americans) that causes a 46% decrease in the DPYD-mediated fluoropyrimidine metabolic rate. The patient was also heterozygous for a SNP in the 3' untranslated region of DPYD (rs12132152), an uncommon variant (MAF = 0.0061 in African-Americans) that has also been associated with fluorouracil toxicity. The severe pancytopenia and high fluorouracil plasma concentration this patient experienced is likely a function of uncommon genetic variants that affect DPYD metabolism. The present data adds to emerging evidence that the Y186C variant is important in patients with African origins who are receiving 5-FU, and future studies should evaluate the consequences of rs12132152 on interindividual variation of DPYD function and its clinical effects on fluoropyrimidine therapy. While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24-31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions.

我们的实验室对临床药物遗传学具有浓厚的兴趣。我们已经在药物开发工作中进行了药物遗传学和药物基因组学（PG）研究，以评估遗传变异对药物代谢，药代动力学（PK），反应和毒性的影响，并了解与已经狭窄的治疗窗口有关的临床临床临床临床变异的贡献。鉴于药物基因组学在精确医学中的重要性，我们积极参与NIH临床中心实施药物基因组学计划。我们已经建立了与药物治疗有关的这些多态性与它们的表型之间的分子联系。 Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein, MDR1), ABCG2 (BCRP), SLCO1B3 (OATP1B3, OATP8), CYP3A4, CYP3A5, CYP1B1, CYP2C19, CYP2D6, UGT1A1, UGT1A9还有其他几个。药物转运蛋白介导多个器官和大多数组织中生物膜跨生物膜的内生物学和异种生物的运动。因此，他们参与了生理学，疾病的发展，药物PK以及最终对无数药物的临床反应。转运蛋白的遗传变异引起人群特异性的药物转运差异，并导致生理学和药物疗法的个体间差异很大。因此，我们有兴趣研究转运蛋白中的遗传变异与疾病病因，疾病状态和疾病的药理治疗有关。我们还对探索大量多态性的非候选基因方法感兴趣，以建立与临床结果的关系，并进行实验以验证探索性扫描引起的潜在致病等位基因。尽管已经进行了许多研究来解释对药代动力学变异性的某些遗传影响，但由于该领域的研究较差，我们也对阐明药效学和治疗结果的遗传标记和治疗结果有浓厚的兴趣。过去，我们曾使用具有代谢酶和转运蛋白（DMET）平台的基因分型患者（在235个基因中确定了1931年的基因型），以探索这些基因与几种癌症疗法的结果之间的潜在联系。在当前财政年度，我们已经过渡到更新的Pharmacoscan平台，该平台在1191 ADME基因中询问了4627个变体。它还检测到4389个祖先信息标记，239个性别标记，7116人类白细胞抗原标记和1484个杀伤细胞免疫球蛋白样受体标记。我们已经研究了许多抗癌剂的PG评估，包括最近的毛霉素，Belinostat，多西他赛/Lenalidomide/Bevacizumab组合，Olaparib/Carboplatin组合，Carfilzomib，Azathioprine，Abiraterone和Paclitaxel。在Cabozantinib对铂 - 抑制性转移性尿路上皮癌患者的II期试验中，我们发现VEGF基因型（1498ct和634cg）与低磷酸血症有关 - 研究中的Cabozantinib的常见3-4级毒性之一。最近，我们在最近的I期临床试验中对患者进行了药物遗传学分析，以研究复发性胶质母细胞瘤和变性星形胶质细胞瘤中的唑唑胺与替莫唑胺结合。 Zotiraciclib由CYP1A2和CYP3A4代谢；从药剂师的结果中，我们确定了基因编码CYP1A2的单核苷酸变化（CYP1A2 5347TC； RS2470890）。该SNP还与13例患者的队列中的Zotiraciclib药代动力学（AUCINF值更高）的显着差异有关。该PK/PG分析确定了一种可能改变Zotiraciclib的PK的多态性，这表明有必要进一步研究基因型引导的给药以降低毒性。结肠的癌症通常接受氟嘧啶治疗，这通常会导致DPYD某些变异的患者严重毒性。中度至有力的证据表明，DPYD中的十种遗传变异与氟嘧啶代谢率的降低有关，至少17种其他DPYD基因型可能会降低DPYD功能。在特定的种族种群中观察到了其中几种变体，并且对特定种族种群的遗传变异性的理解对于氟吡啶毒性毒性的未来降低至关重要。我们提出了一份案例报告，其中一名非洲裔美国患者接受了FOLFOX治疗的结直肠恶性肿瘤，该治疗期间在治疗过程中患上了深厚的全年政体。 Pharmacoscan分析确定了患者的DPYD Y186C变体（RS115232898），这是一种罕见的等位基因（非裔美国人的次要等位基因频率（MAF）= 0.032），导致DPYD介导的氟亚胺代谢率降低了46％。该患者在3'未翻译的DPYD区域（rs12132152）中也是杂合的，这是一种罕见的变体（非裔美国人的MAF = 0.0061），这也与氟尿嘧啶毒性有关。该患者所经历的严重的全年症和高氟尿嘧啶血浆浓度可能是影响DPYD代谢的不常见遗传变异的功能。目前的数据增加了新的证据，表明Y186C变体在接受5-FU的非洲起源的患者中很重要，并且未来的研究应评估Rs12132152对DPYD功能及其临床对荧光酰亚胺治疗的临床影响的后果。虽然超过100阶段的研究在肿瘤学上发表了，但这些研究中不到1％的研究基于影响药理学的遗传变异来对患者进行分层。基于药物遗传学的患者分层可以通过鉴定出较小的发展毒性的反应性患者来改善临床试验的成功；但是，第一阶段研究设计所施加的科学限制减少了这些研究得出结论的潜力。我们用药物遗传学终点（n = 84），评估毒性（n = 42），反应或PFS（n = 32）和药代动力学（n = 40），对肿瘤学的所有阶段研究进行了汇编。这些研究中的大多数都集中在有限数量的药物类别上：拓扑异构酶抑制剂，抗代谢物和抗血管生成剂。 确定了八个基因型定向的I期研究。第一阶段的研究包括具有多种合并症，先前疗法，种族背景和其他因素的统计分析的同质种群。综上所述，本文分析的I期研究对少量患者（中位数为95％CI = 28，24-31），评估了很少有已知会改变表型的变体，几乎没有提供药物遗传学假设的理由。未来的研究应在研究设计期间考虑这些因素，以优化I期研究的成功并回答重要的科学问题。