Pharmacogenomics of Erlotinib

描述(申请人提供)：埃洛替尼(OSI-774，Tarceva)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癌症的治疗。尽管有关厄洛替尼的临床药理、毒性和活性方面的知识很多，但关于哪个因素(S)决定药物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吉非替尼的显著敏感性有关，吉非替尼是一种作用机制与Erlotinib相似的药物，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。预测其他疾病反应的因素尚不清楚，如头颈部鳞状细胞癌(SCCHN)，在这些疾病中尚未发现突变。在到目前为止进行的研究中，已经观察到皮疹的发展与更高的应答率和更高的存活率相关。对这种联系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容易受到药物的毒性和抗肿瘤作用的影响。EGFR在基因的内含子1中有一个高度多态的单片段CA二核苷酸重复序列，它调节基因的转录。我们课题组进行的初步研究表明，这种多态性与Erlotinib的活性有关。这项研究将检验这样一个假设，即CA重复次数不同的受试者对Erlotinib的反应不同。具体目的是：1)评估在EGFR基因内含子1不同CA重复数的SCCHN患者中厄洛替尼的应答率、进展时间和毒性(皮疹)；2)比较厄洛替尼在这些患者系列皮肤活检中的药效学效应。我们将在两组SCCHN患者中进行前瞻性的II期临床研究，短(16/16)或长(16/20或20/20)CA二核苷酸重复序列的患者将接受厄洛替尼150 mg/天的治疗。将确定皮肤活检中的应答率、肿瘤进展时间、皮疹、抑制EGFR和上调p27。将测量血浆中总埃洛替尼和游离埃洛替尼的水平，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.