A pharmacogenetic and pharmacodynamic study of erlotinib

描述(申请人提供)：厄洛替尼(OSI-774)是一种表皮生长因子受体(EGFR)酪氨酸激酶的小分子抑制剂。OSI-774，像其他EGFR指导的疗法一样，与包括皮疹和腹泻在内的毒性有关。这些毒性的分子基础以及患者之间高度毒性变异性的基础尚未确定。表皮和胃肠道黏膜的基底层都表达EGFR，EGFR信号在这些组织中参与了生理调节。由于最近的几项研究表明，皮疹可能与抗肿瘤活性有关，所以使用EGFR导向疗法的患者的皮肤毒性可能具有特殊的临床意义。我们推测，在非恶性组织中抑制EGFR依赖的信号转导可能是OSI-774毒性的原因，并可能是潜在抗肿瘤疗效的临床相关指标。这项研究将包括在大约晚期实体瘤患者中以固定的起始剂量给予OSI-774。将进行几项分析，以评估患者间毒性差异的潜在原因。EGFR基因第一内含子CA二核苷酸重复序列的长度与EGFR的相对表达密切相关。具体目标1将是一项药物遗传学分析，测试该序列多态的长度可能作为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，评估相对的EGFR表达和激活，以及在使用OSI-774之前和之后的皮肤活检组织中下游丝裂原激活的激酶ERK1和ERK2的表达和激活。这些分析将检验CA二核苷酸重复长度与EGFR依赖信号的相对抑制程度相关的假设。具体目标3将是一项药代动力学分析，评估CYP3A5代谢酶基因的多态是否与OSI-774代谢指标相关。这些分析将共同描述影响OSI-774毒性的患者间变异性的潜在因素。清楚地了解OSI-774和类似的EGFR导向药物毒性变化的基础可能最终指导最有可能受益的患者使用目前可用的药物。确定这种毒性的基础也可以促进EGFR导向药物的开发，这些药物可以避免这种毒性，或者对更广泛的癌症患者有效。

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.