Determinants of Response to ZD1839 (1 R01-CA104900-01)

描述（由申请人提供）：表皮生长因子受体（EGFR）在大多数表皮癌患者中不受调节，已成为癌症治疗药物开发的一个有吸引力的靶点。ZD1839是EGFR的小分子抑制剂。尽管对该药物的临床药理学、毒性和活性有了重要的了解，但关于哪些因素决定对这类药物的易感性的基本问题仍然知之甚少。迄今为止进行的研究表明，EGFR的表达并不能很好地预测这些药物的活性。更好地理解这个问题将有助于将ZD1839靶向到更有可能从该药获益的患者身上。本提案的总体目标是合理开发对ZD1839反应的决定因素。该研究的中心假设是，ZD1839在EGFR功能改变的肿瘤中特别活跃，其中该药物抑制受体的激活和信号传导。具体目标是：1)开发ZD1839的药物诊断测试；2)开发并验证ZD1839在正常代孕组织中的药效学试验。为了实现这一目标，我们将采用一种新的临床试验设计，其中计划接受术前放化疗联合ZD1839的II期和III期直肠癌患者将在开始联合治疗部分之前的15天先导期接受单一药物ZD1839。在ZD1839引入治疗之前和之后，将对肿瘤组织（通过内窥镜程序容易获得）和正常皮肤组织进行活检。口腔粘膜涂片也将被收集。通过对ZD1839的生物学、代谢和毒理学反应来测定EGFR的表达和激活、EGFR内含子1区多态性与ZD1839的作用之间的关系。将评估药物在正常和肿瘤组织中的药效学效应与生物和代谢活性测量之间的相关性。这些结果将为基于生物学和机理数据的这类新型药物的临床开发提供重要信息。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is deregulated in the majority of patients with epidermal cancers and has become an attractive target for the development of cancer therapeutics. ZD1839 is a small molecule inhibitor of the EGFR. Despite the significant knowledge acquired with regards to the clinical pharmacology, toxicity, and activity of this drug, the fundamental question regarding which factor (s) determine susceptibility to this class of agents remain poorly understood. Studies conducted thus far suggest that the expression of the EGFR is not a good predictor of the activity of these drugs. A better understanding of this question would facilitate targeting ZD1839 to patients more likely to benefit from the drug. The overall objective of this proposal is to rationally develop determinants of response to ZD1839. The central hypothesis of the proposed research is that ZD1839 will be particularly active in tumors with altered EGFR function in which the agent inhibits the activation and signaling of the receptor. The Specific Aims are to 1) develop a pharmacodiagnostic test for ZD1839; and, 2) develop and validate a pharmacodynamic test of ZD1839 effects in normal surrogate tissues. To accomplish this goal we will use a novel clinical trial design in which patients with stage II and III carcinoma of the rectum scheduled to undergo pre-operative chemoradiation in combination with ZD 1839 will receive single agent ZD1839 for a lead-in period of fifteen days prior to commencing the combined modality treatment segment. Biopsies of tumors tissues (easily accessible by endoscopic procedures), and normal skin tissues will be performed prior to treatment and after the lead-in treatment with ZD1839. Smears from oral mucosa will also be collected. The relationship between the expression and activation of the EGFR, polymorphisms in the intron 1 region of the EGFR gene and the effects of ZD1839 as measured by biological, metabolic, and toxicological response to ZD1839 will be determined. Correlations between the pharmacodynamic effects of the drug in normal and tumor tissues with measurements of biological and metabolic activity will be evaluated. These results will provide important information for the rationale clinical development of this class of novel agents based on biologic and mechanistic data.