A pharmacogenetic and pharmacodynamic study of erlotinib

厄洛替尼的药物遗传学和药效学研究

• 批准号: 6741436
• 负责人: Charles M. Rudin
• 金额: $ 18.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741436
• 关键词: antineoplastics; biological signal transduction; biopsy; clinical research; clinical trial phase I; cytochrome P450; dinucleotide; drug adverse effect; drug metabolism; epidermal growth factor; genetic markers; genetic polymorphism; growth factor receptors; human subject; human therapy evaluation; immunocytochemistry; inhibitor /antagonist; mitogen activated protein kinase; neoplasm /cancer chemotherapy; patient oriented research; pharmacogenetics; pharmacokinetics; quinazolines; toxicology

DESCRIPTION (provided by applicant): Erlotinib (OSI-774) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. OSI-774, like other EGFR-directed therapies, is associated with toxicities including skin rash and diarrhea. The molecular basis of these toxicities, and the basis for the high degree of interpatient variability in toxicity, has not been determined. Basal layers of both the epidermis and the gastrointestinal mucosa express EGFR, and EGFR signaling has been implicated in physiological regulation in these tissues. Skin toxicity in patients treated with EGFR-directed therapies may be of particular clinical relevance as several recent studies have suggested that skin rash may correlate with anti-tumor activity. We hypothesize that inhibition of EGFR-dependent signal transduction in non-malignant tissues may be responsible for OSI-774 toxicity, and may be a clinically relevant indicator of potential anti-tumor efficacy. This study will involve the administration of OSI-774 at a fixed starting dose in approximately 64 subjects with advanced solid tumors. Several analyses will be performed to assess potential causes of interpatient variability in toxicity. Length of a CA dinucleotide repeat polymorphism in the first intron of the EGFR gene has been strongly correlated with relative expression of EGFR. Specific Aim 1 will be a pharmacogenetic analysis, testing the hypothesis that length of this sequence polymorphism may serve as a predictor of OSI-774 toxicity in vivo. Specific Aim 2 will be a pharmacodynamic analysis, evaluating relative EGFR expression and activation, as well as expression and activation of the downstream mitogen activated kinases ERK1 and ERK2 in skin biopsies prior to and following administration of OSI-774. These analyses will test the hypothesis that CA dinucleotide repeat length correlates with relative degree of suppression of EGFR-dependent signaling. Specific Aim 3 will be a pharmacokinetic analysis, evaluating whether polymorphisms in the CYP3A5 metabolizing enzyme gene correlate with measures of OSI-774 metabolism. Together these analyses will characterize potential factors influencing interpatient variability in OSI-774 toxicity. A clear understanding of the basis of variability in the toxicity of OSI-774 and similar EGFR-directed agents might ultimately guide use of the currently available agents to patients most likely to benefit. Defining the basis of this toxicity could also promote the development of EGFR-directed agents that may avoid such toxicity or that may be effective in a broader spectrum of cancer patients.

描述（由申请人提供）：Erlotinib（OSI-774）是表皮生长因子受体（EGFR）酪氨酸激酶的小分子抑制剂。与其他EGFR指导的疗法一样，OSI-774与包括皮疹和腹泻在内的毒性有关。尚未确定这些毒性的分子基础，以及高度毒性介入介质的基础。表皮和胃肠道粘膜表达EGFR的基础层和EGFR信号传导与这些组织的生理调节有关。通过EGFR指导疗法治疗的患者的皮肤毒性可能特别临床相关，因为最近的一些研究表明皮疹可能与抗肿瘤活性相关。我们假设抑制非理性组织中EGFR依赖性信号转导可能是OSI-774毒性的原因，并且可能是潜在的抗肿瘤功效的临床相关指标。这项研究将涉及大约64名患有晚期实体瘤的受试者的固定起始剂量的OSI-774。将进行几项分析，以评估毒性插入术变异性的潜在原因。 EGFR基因的第一个内含子中Ca二核苷酸重复多态性的长度与EGFR的相对表达密切相关。具体目标1将是药物遗传学分析，检验了以下假设：该序列多态性的长度可以作为OSI-774毒性的预测指标。具体的目标2将是药效分析，评估相对EGFR的表达和激活，以及在OSI-774施用之前和之后，在皮肤活检中，下游有丝分裂原激活激活的激活激活激活的激活激活的ERK1和激活。这些分析将检验以下假设：CA二核苷酸重复长度与EGFR依赖性信号传导的相对抑制程度相关。具体目标3将是药代动力学分析，评估CYP3A5代谢酶基因基因中的多态性是否与OSI-774代谢的测量相关。这些分析将共同表征影响OSI-774毒性室内变异性的潜在因素。对OSI-774毒性和类似EGFR指导药物的毒性可变性基础的明确理解最终可能指导使用当前可用的药物对最有可能受益的患者使用。定义这种毒性的基础也可以促进EGFR指导的药物的发展，而EGFR指导的药物可能避免这种毒性，或者可能在较广泛的癌症患者中有效。