Pharmacogenomics of Erlotinib

描述（由申请人提供）：厄洛替尼（OSI-774，特罗凯）是一种表皮生长因子受体（EGFR）的小分子抑制剂，目前正在临床开发中，用于治疗癌症。尽管关于厄洛替尼的临床药理学、毒性和活性的知识很多，但关于哪些因素决定对药物的敏感性的基本问题仍然知之甚少。最近发现EGFR激酶结构域的突变与对吉非替尼（一种与厄洛替尼具有相似作用机制的药物）的显著易感性相关，这解释了为什么一组非小细胞肺癌患者对该药物反应良好。预测其他疾病（如未发现突变的头颈部鳞状细胞癌（SCCHN））反应的因素尚不清楚。在迄今为止进行的研究中，已经观察到皮疹的发展与更高的反应率和生存率增加相关。这种关联的一个潜在解释可能是，正常组织和肿瘤组织之间共有的遗传因素使这些组织分别易受药物的毒性和抗肿瘤作用的影响。EGFR在基因的内含子1中具有高度多态性的单片段CA二核苷酸重复，已知其调节基因的转录。我们小组进行的初步研究表明，这种多态性与厄洛替尼的活性有关。本研究将检验具有不同数量CA重复的受试者对厄洛替尼的反应不同的假设。具体目标是：1）在EGFR基因内含子1中具有不同数量CA重复序列的SCCHN患者中估计厄洛替尼的缓解率、进展时间和毒性（皮疹），2）在这些患者的连续皮肤活检中比较厄洛替尼的药效学作用。我们将在两组SCCHN患者中进行前瞻性II期临床研究，短（16/16）或长（16/20或20/20）CA二核苷酸重复将接受150 mg/天的厄洛替尼治疗。将确定缓解率、肿瘤进展时间、皮疹、EGFR抑制和皮肤活检中p27上调。将测量总厄洛替尼和游离厄洛替尼的血浆水平，以排除预期差异的药理学基础。这项研究将确定厄洛替尼的药理学作用是否可能有遗传基础。

DESCRIPTION (provided by applicant): Erlotinib (OSI-774, Tarceva) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) currently in clinical development for the treatment of cancer. Despite the significant knowledge with regards to the clinical pharmacology, toxicity, and activity or Erlotinib, the fundamental question regarding which factor (s) determine susceptibility to the drug remain poorly understood. The recent discovery that mutations in the EGFR kinase domain are associated with marked susceptibility to Gefitinib, a drug with similar mechanism of action as Erlotinib, explains why a set of patients with non small cell lung cancer respond very well to the drug. Factors that predict response in other diseases such as squamous cell carcinoma of the head and neck (SCCHN) in which no mutations have been found are not known. In studies conducted thus far, it has been observed that the development of cutaneous rash is associated with higher response rate and increased survival. A potential explanation for this association could be that genetic factors that are shared between normal and tumor tissues predispose such tissues to the toxic and antitumor effects of the drug, respectively. The EGFR has a highly polymorphic single segment CA dinucleotide repeat in the intron 1 of the gene that is known to regulate transcription of the gene. Preliminary studies conducted by our group suggest that this polymorphism is related to the activity of Erlotinib. This study will test the hypothesis that subjects with different number of CA repeats respond differently to Erlotinib. The specific aims are: 1) estimate the response rate, time to progression, and toxicity (skin rash) of Erlotinib in patients with SCCHN with different number of CA repeats in intron 1 of the EGFR gene and 2) compare the pharmacodynamic effects of Erlotinib in serial skin biopsies of these patients. We will conduct a prospective phase II clinical study in two groups of patients with SCCHN and short (16/16) or long (16/20 or 20/20) CA dinucleotide repeat will receive 150 mg/day of Erlotinib. The response rate, time to tumor progression, skin rash, inhibition of EGFR and upregulation of p27 in skin biopsies will be determined. Plasma levels of total and free Erlotinib will be measured to rule out pharmacological bases for the expected differences. This study will determine whether a genetic basis for the pharmacological effects of Erlotinib is likely.