ZD1839 Therapy of Glioblastoma Multiforme

描述（由申请人提供）：尽管数十年的密集 神经系统（CNS）肿瘤的发病率仍然很低。成人的中位生存期 最常见的CNS肿瘤形式，脑胶质母细胞瘤，是8-12 诊断后几个月。对单一或多个药剂的偶尔反应 化疗是在复发性肿瘤的背景下看到的，但这些反应 通常持续时间很短，治愈率很低。代理人的识别 有效对抗神经胶质恶性肿瘤是具有挑战性的，迄今为止还没有药物测试 在大多数接受治疗的患者中可靠地产生反应。基因 已发现与胶质瘤恶性程度增加相关的扩增 发生在大约50%的多形性胶质母细胞瘤（GBM）中， 例尽管N-myc和gli的扩增（总体为2- 4%）已经被证实是一种基因突变， 这些基因和c-myc或K-ras的扩增 与c-erb 1的扩增相比， 表皮生长因子（EGFR）基因。EGFR基因大小为110 kb，26个外显子， 组织，定位于染色体臂7 -13。首先是 Libermann等（1985）对EGFR基因扩增的最初描述， 随后的研究证实，大约37- 58%的GBM， 只有孤立的间变性星形细胞瘤，扩增EGFR基因。ZD 1839是一种 EGFR酪氨酸激酶的有效体外抑制剂，与ATP竞争，和 与肽底物无竞争性。ZD 1839可抑制 EGF刺激的KB口腔鳞癌细胞。这种效果很容易 在移除化合物时可逆。酶抑制似乎是 选择性，对其他测试激酶几乎没有活性。生长抑制 在裸鼠体内的多种人类肿瘤异种移植模型中， 在12.5 - 200 mg/kg每日一次经口给药范围内证实 最多4个月。在一些已经确定的肿瘤治疗中， ZD 1839产生了显著的回归。从异种移植研究来看， 但很清楚EGFR表达水平与 抗肿瘤反应这项建议的具体目标是：1）确定 ZD 1839治疗成人胶质母细胞瘤的活性和毒性 第一次复发时的多形性; 2）确定是否定性和定量 基因型和表型EGFR表达水平可预测GBM对 ZD1839

DESCRIPTION (Provided by applicant): Despite decades of intensive nervous system (CNS) neoplasms remains very poor. Median survival for adults with the most common form of CNS tumor, the cerebral glioblastoma, is 8-12 months after diagnosis. Occasional responses to single or multiple agent chemotherapy are seen in the setting of recurrent tumor, but these responses are generally of short duration, and cures are rare. Identification of agents active against glial malignancies is challenging, with no drug tested to date reliably producing responses in a majority of treated patients. Gene amplification, related to increasing grade of glioma malignancy, has been found to occur in approximately 50 percent of all glioblastoma multiforme (GBM) cases. Although amplification of N-myc and gli (2-4 percent overall) has been reported by different groups, amplification of these genes and c-myc or K-ras are considered sporadic as compared to the amplification of c-erb 1, or the epidermal growth factor (EGFR) gene. The EGFR gene, 110 kb in size, 26 exons in organization, is localized to chromosome arm 7pll-13. Beginning with the initial description of EGFR gene amplification by Libermann et al (1985), subsequent studies have confirmed that approximately 37-58 percent of GBMs, but only isolated anaplastic astrocytomas, amplify the EGFR gene. ZD 1839 is a potent inhibitor in vitro of EGFR tyrosine kinase, competitive with ATP, and noncompetitive with peptide substrate. ZD 1839 inhibits the proliferation of EGF-stimulated KB oral squamous carcinoma cells. This effect is readily reversible on removal of the compound. Enzyme inhibition appears to be selective, with little activity against other kinases tested. Growth inhibition in vivo of a wide variety of human tumour xenograft models in nude mice was demonstrated at a range of once daily, oral doses between 12.5 and 200 mg/kg per day for up to 4 months. In some already established tumours treatment with ZD 1839 produced significant regressions. From the xenograft studies, it is not yet clear if there is a correlation between the level of EGFR expression and antitumor response. The specific aims of this proposal are: 1) To identify the activity and toxicity of ZD 1839 in the treatment of adults with glioblastoma multiforme in first relapse; 2) to determine if qualitative and quantitative levels of genotypic and phenotypic EGFR expression predict response of GBM to ZD 1839.