Pharmacogenomics of Erlotinib

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， 目前在临床开发中用于治疗癌症。尽管我们知道 厄洛替尼的临床药理学、毒性和活性，关于厄洛替尼 决定药物敏感性的因素仍然知之甚少。最近发现突变 在EGFR激酶结构域中，与对吉非替尼的显著易感性相关，吉非替尼是一种具有类似 Erlotinib的作用机制，解释了为什么一组非小细胞肺癌患者 对药物很好。预测其他疾病反应的因素，如鳞状细胞癌， 没有发现突变的头颈部（SCCHN）是未知的。进行的研究中 到目前为止，已经观察到皮疹的发生与较高的反应相关， 提高生存率。对这种关联的一个潜在解释可能是， 在正常组织和肿瘤组织之间共享的蛋白质使这样的组织易于受到抗肿瘤药物的毒性和抗肿瘤作用的影响。 药，分别。EGFR基因内含子中有一个高度多态的单片段CA二核苷酸重复序列 1的基因，已知该基因调节该基因的转录。我们小组进行的初步研究 提示该多态性与厄洛替尼的活性相关。本研究将验证这一假设， 具有不同数目CA重复的受试者对厄洛替尼的反应不同。具体目标是：1） 估计厄洛替尼在SCCHN患者中的缓解率、进展时间和毒性（皮疹） 在EGFR基因的内含子1中具有不同数目的CA重复序列，和2）比较 在这些患者的连续皮肤活检中观察厄洛替尼的作用。我们将进行一项前瞻性的II期临床试验， 在两组SCCHN和短（16/16）或长（16/20或20/20）CA二核苷酸患者中进行的研究 重复将接受150 mg/天的厄洛替尼。反应率，肿瘤进展时间，皮疹， 将测定皮肤活检中EGFR的抑制和p27的上调。血浆中的总浓度和 将测量游离厄洛替尼以排除预期差异的药理学基础。本研究 将确定是否可能存在厄洛替尼药理学作用的遗传基础。

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 know 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 tesl 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.