INHIBITION OF HEPARIN-BINDING GROWTH FACTORS AND ANGIOGENESIS

抑制肝素结合生长因子和血管生成

• 批准号: 3751878
• 负责人: ANTON WELLSTEIN
• 金额: --
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3751878
• 关键词: RNase protection assay; angiogenesis; antineoplastics; athymic mouse; biomarker; cell cycle proteins; complementary DNA; drug interactions; drug screening /evaluation; fibroblast growth factor; gene expression; glioma; heparin; hormone inhibitor; human subject; human tissue; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic process; neoplastic transformation; polymerase chain reaction; prognosis; vascular endothelium

Sustained tumor growth requires paracrine signals between the tumor cells and the normal surrounding host tissue. One crucial function of these signals is to recruit endothelial cells and thus new blood vessels for the nourishment of the expanding tumor mass. Abundant neovascularization is a characteristic of highly malignant glioblastoma multiforme. This tumor-induced proliferation and migration of endothelial cells contrasts with the extremely low turn-over rate of endothelial cells in the healthy adult. It is thus conceivable that a selective blockade of endothelial cell proliferation should inhibit tumor growth with only few adverse effects. We found that the most effective endothelial cell growth factors released from cancer cells in vitro are heparin-binding growth factors (HBGFs) and we have therefore focused our search for inhibitors of HBGFs on heparin- like polysulfates. We have demonstrated that HBGF action in vitro can be blocked by a structural analogue of heparin: pentosanpolysulfate (PPS). Furthermore, the growth of human cancer cell lines into subcutaneous tumors in athymic nude mice can be inhibited by the treatment of the animals with PPS. PPS was effective against tumors derived from in vitro PPS-sensitive and from in vitro PPS-resistant tumor cell lines. These data suggest that PPS blocks the hosts' reaction to the HBGF(s) released from the tumor cells. A phase I trial in cancer patients was prompted by these preclinical studies. In an independent approach, we show that the endothelial cell inhibitor AGM 1470 can prevent angiogenesis induced by benign tumors (e.g. schwannomas) as well as by glioblastomas and inhibit tumor progression in vivo. We propose the following studies: 1. To probe for expression of known HBGF genes in normal and cancerous brain tissues as potential molecular markers of the progression and prognosis of the disease as well as markers of a potential therapeutic response to an HBGF-targeted therapy. 2. To determine to what extent endothelial cell proliferation in normal and cancerous brain tissues can serve as a biological indicator of the disease state, prognosis of the patient and responsiveness to therapy. 3. To study PPS and new synthetic heparinoids as HBGF-inhibitors. In particular, to find analogues with improved therapeutic index that act on brain tumors in vivo. 4. To study the novel endothelial cell inhibitor AGM 1470 for its ability to inhibit growth of brain tumors alone and combined with PPS.

持续的肿瘤生长需要肿瘤细胞之间的旁分泌信号 以及正常的周围宿主组织。 这些关键功能 信号是招募内皮细胞，因此 肿瘤肿块扩张的营养。 丰富的新血管形成 是高度恶性胶质母细胞瘤多形的特征。 这 肿瘤诱导的内皮细胞的增殖和迁移是对比的 在健康中，内皮细胞的转折率极低 成人。 因此，可以想象的是内皮的选择性封锁 细胞增殖应仅抑制肿瘤的生长 效果。 我们发现最有效的内皮细胞生长因子释放 体外癌细胞是肝素结合生长因子（HBGF）和 因此，我们将寻找HBGF抑制剂的搜索集中在肝素上 像多硫酸盐。 我们已经证明了体外HBGF动作可以 被肝素的结构类似物阻塞：五桑乳硫酸盐 （pps）。 此外，人类癌细胞系的生长 无胸腺裸鼠的皮下肿瘤可以抑制 用PPS治疗动物。 PPS有效抵抗肿瘤 源自体外PPS敏感和体外PPS肿瘤 细胞系。 这些数据表明PPS阻止了主机对 HBGF（S）从肿瘤细胞中释放出来。 癌症I期试验 这些临床前研究提示患者。 独立 方法，我们表明内皮细胞抑制剂AGM 1470可以 还可以防止良性肿瘤（例如schwannomas）诱导的血管生成 如胶质母细胞瘤和抑制体内肿瘤进展。 我们提出以下研究：1。探测已知的表达 正常和癌性脑组织中的HBGF基因作为潜在的分子 疾病进展和预后的标志 对HBGF靶向治疗的潜在治疗反应的标志物。 2。确定正常内皮细胞增殖的程度 癌性脑组织可以作为 疾病状态，患者的预后和对治疗的反应。 3。研究PPS和新的合成肝素作为HBGF抑制剂。 在 特别是，找到具有改进的治疗指数的类似物 在体内脑肿瘤上。 4。研究新型内皮细胞 抑制剂AGM 1470抑制脑肿瘤生长的能力 单独并与PPS结合。