Albanell J, Rojo F, Baselga J
Medical Oncology Service, Vall d'Hebron Hospital, Barcelona, Spain.
Semin Oncol. 2001 Oct;28(5 Suppl 16):56-66. doi: 10.1016/s0093-7754(01)90283-0.
ZD1839 is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Based on its promising preclinical antitumor activity and favorable toxicity profile, ZD1839 has recently entered clinical trials. A particular challenge in the clinical development of this exciting compound is to explore its biological (pharmacodynamic) activity against the EGFR and receptor-dependent processes in serial biopsies. Such studies might be of assistance in predicting the subset of tumors that will benefit from therapy. They also may prove whether complete EGFR blockade is achieved in vivo. This latest point is particularly relevant because an optimal biological dose (ie, a dose resulting in complete receptor inhibition) would be preferred to the maximally tolerated dose that is being used with conventional nontargeted chemotherapeutic drugs. A series of preclinical studies have identified potentially useful surrogate markers of EGFR activity (eg, phosphorylation of EGFR and downstream receptor-dependent molecules such as mitogen-activated protein kinase [MAPK], Akt, or p27) that could be used as a surrogate marker of ZD1839 efficacy. In various tumor types, such as head and neck squamous carcinoma and gastric and breast adenocarcinoma, a relationship between EGFR and downstream markers (such as phosphorylated MAPK) has been characterized, further supporting the potential of these molecules for pharmacodynamic studies. Preliminary analysis of serial skin biopsies from patients participating in phase I trials has shown that ZD1839 results in substantial changes in EGFR-dependent molecules, such as phosphorylated MAPK, p27, phosphorylated STAT3, and others. Based on these encouraging results, studies assessing activated EGFR, activated MAPK, and other selected markers in phase II trials in tumors from patients treated with ZD1839 are currently planned or ongoing.
ZD1839是一种口服活性、选择性表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，可阻断与癌细胞增殖和存活以及促进癌症生长的其他宿主依赖性过程相关的信号转导途径。基于其有前景的临床前抗肿瘤活性和良好的毒性特征，ZD1839最近已进入临床试验。这种令人兴奋的化合物临床开发中的一个特殊挑战是在系列活检中探索其针对EGFR和受体依赖性过程的生物学（药效学）活性。此类研究可能有助于预测将从治疗中获益的肿瘤亚组。它们还可能证明体内是否实现了完全的EGFR阻断。这最后一点尤为重要，因为与传统的非靶向化疗药物所使用的最大耐受剂量相比，最佳生物学剂量（即导致受体完全抑制的剂量）将更为可取。一系列临床前研究已经确定了EGFR活性的潜在有用替代标志物（例如EGFR和下游受体依赖性分子如丝裂原活化蛋白激酶[MAPK]、Akt或p27的磷酸化），这些标志物可作为ZD1839疗效的替代标志物。在各种肿瘤类型中，如头颈部鳞状细胞癌、胃腺癌和乳腺腺癌，EGFR与下游标志物（如磷酸化MAPK）之间的关系已得到表征，进一步支持了这些分子用于药效学研究的潜力。对参与I期试验患者的系列皮肤活检的初步分析表明，ZD1839会导致EGFR依赖性分子如磷酸化MAPK、p27、磷酸化STAT3等发生显著变化。基于这些令人鼓舞的结果，目前正在计划或正在进行评估接受ZD1839治疗患者肿瘤中活化EGFR、活化MAPK和其他选定标志物的II期试验。
