Specific inhibition of heat-shock-protein 90 (Hsp90) by a novel peptidomimetic inhibitor shepherdin in malignant glioma cells

恶性胶质瘤是最常见的脑肿瘤类型。胶质瘤的最常见和恶性形式被称为多形性胶质母细胞瘤（GBM），约占病例的60%-70%。目前GBM的标准治疗方法的中位生存期仅为14.6个月。热休克蛋白90（Hsp 90）是一个有吸引力的治疗靶点，因为它可以结合许多充分表征的客户蛋白，包括许多致癌信号传导蛋白，其对于GBM的进展和治疗抗性是必需的，如ErbB 2、EGFR、Raf、MEK、PDGFR、Cdk-4、Cdk- 6和Cdk-9、Akt、突变的p53和存活素。这些蛋白质中的许多是在GBM中突变或过表达的蛋白质。Hsp 90的一种新的特异性抑制剂是肽模拟物Shepherdin，其已被证明特异性靶向肿瘤细胞，而对非肿瘤细胞没有影响。在这项研究中，Shepherdin将被评估为治疗GBM的潜在新药。

Malignant gliomas are the most common type of brain tumors. The most common and malignant form of gliomas is known as glioblastoma multiforme (GBM), which accounts for approximately 60%–70% of the cases. Current standard-of-care therapy for GBM confers a median survival period of only 14.6 months. Heat-shock-protein 90 (Hsp90) is an attractive therapeutic target since it can bind a number of well-characterized client proteins, including many oncogenic signaling proteins being essential for progression and therapeutic resistance of GBM such as ErbB2, EGFR, Raf, MEK, PDGFR, Cdk-4, - 6, and -9, Akt, mutated p53 and survivin. Many of these proteins are the ones that are mutated or overexpressed in GBM. A novel specific inhibitor of Hsp90 is the peptidomimetic Shepherdin that has been shown to specifically target tumour cells whereas it has no effect on non-neoplastic cells. In this study Shepherdin will be evaluated as a potential new drug in treating GBM.