A pharmacogenetic and pharmacodynamic study of erlotinib

性状（由申请方提供）：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与其他EGFR导向疗法一样，与皮疹和腹泻等毒性相关。尚未确定这些毒性的分子基础以及毒性的高度患者间变异性的基础。表皮和胃肠道粘膜的基底层表达EGFR，EGFR信号传导与这些组织中的生理调节有关。EGFR导向疗法治疗患者的皮肤毒性可能具有特殊的临床意义，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，抑制EGFR依赖性信号转导在非恶性组织可能是负责OSI-774毒性，并可能是一个潜在的抗肿瘤疗效的临床相关指标。本研究将涉及在约64例晚期实体瘤受试者中以固定起始剂量给予OSI-774。将进行几项分析，以评估患者间毒性变异性的潜在原因。EGFR基因第一内含子中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，检验该序列多态性的长度可作为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，评价OSI-774给药前后皮肤活检中相对EGFR表达和活化，以及下游促分裂原活化激酶ERK 1和ERK 2的表达和活化。这些分析将检验CA二核苷酸重复序列长度与EGFR依赖性信号转导抑制的相对程度相关的假设。具体目标3是药代动力学分析，评价CYP 3A 5代谢酶基因多态性是否与OSI-774代谢指标相关。这些分析将共同表征影响OSI-774毒性的患者间变异性的潜在因素。对OSI-774和类似EGFR导向药物毒性变异性基础的清楚理解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，或者可以在更广泛的癌症患者中有效。

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.