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: 6646955
• 负责人: CHARLES M RUDIN
• 金额: $ 21.27万
• 依托单位: UNIVERSITY OF CHICAGO
• 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 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646955
• 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）：厄洛替尼（OSI-774）是表皮生长因子受体（EGFR）酪氨酸激酶的小分子抑制剂。 OSI-774 与其他 EGFR 导向疗法一样，与皮疹和腹泻等毒性相关。这些毒性的分子基础以及患者间毒性高度差异的基础尚未确定。表皮和胃肠粘膜的基底层均表达 EGFR，并且 EGFR 信号传导参与这些组织的生理调节。接受 EGFR 靶向治疗的患者的皮肤毒性可能具有特殊的临床相关性，因为最近的几项研究表明皮疹可能与抗肿瘤活性相关。我们假设非恶性组织中 EGFR 依赖性信号转导的抑制可能是 OSI-774 毒性的原因，并且可能是潜在抗肿瘤功效的临床相关指标。这项研究将涉及以固定起始剂量对大约 64 名晚期实体瘤受试者施用 OSI-774。将进行多项分析来评估患者间毒性差异的潜在原因。 EGFR基因第一个内含子中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，测试该序列多态性的长度可以作为 OSI-774 体内毒性的预测因子的假设。具体目标 2 将是药效学分析，评估施用 OSI-774 之前和之后皮肤活检中的相对 EGFR 表达和激活，以及下游丝裂原激活激酶 ERK1 和 ERK2 的表达和激活。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 代谢酶基因的多态性是否与 OSI-774 代谢测量相关。这些分析将共同描述影响 OSI-774 毒性的患者间差异的潜在因素。清楚地了解 OSI-774 和类似 EGFR 导向药物的毒性变异性基础可能最终指导最有可能受益的患者使用当前可用的药物。定义这种毒性的基础还可以促进针对 EGFR 的药物的开发，这些药物可以避免这种毒性或可能对更广泛的癌症患者有效。