Indirubins: novel anti-invasive and anti-angiogenic drugs for malignant gliomas

描述(由申请人提供)：我们试图确定蓝宝石(IRS)，一类对糖原合成酶激酶-3(GSK-3)具有相对选择性抑制活性的化学物质，是否显示出抗恶性胶质瘤的活性。这些肿瘤仍然是最难治疗的癌症之一，特别是因为它们有侵袭和渗透到正常大脑的倾向。根据数据显示，使用锂，一种GSK-3抑制剂，FDA批准用于治疗双相情感障碍，在体外降低胶质瘤的活力，我们已经启动了一项双机构2期临床试验，在新诊断的恶性胶质瘤患者的标准细胞毒治疗中添加锂，以确定它是否会减少胶质瘤的侵袭性。然而，锂的治疗指数很窄，对GSK-3的抑制活性也没有那么特异。因此，我们筛选了其他GSK-3抑制剂，发现IRS比锂更有效，在胶质瘤小鼠模型中似乎耐受性良好。我们的初步数据显示，IRS：a-比锂更有效地抑制糖原合成酶-3(GSK-3)的活性；b-导致β-连环蛋白从膜到细胞核的移位；c-改变几个与细胞间黏附和侵袭有关的连环蛋白反应基因的表达，包括claudin-1，d-显著降低胶质瘤细胞的体外和体外侵袭。 在体内；e-减少胶质瘤中的微血管数量；以及f-减少内皮运动，至少在体外是这样。IR治疗显著提高了原位胶质瘤动物的存活率，并减少了异位侧脑胶质瘤的体积。因此，我们建议进一步研究IRS，以提供与其疗效和毒性相关的临床前数据，并了解其在胶质瘤启动细胞(GIC)而不是细胞系中的作用机制。我们的总体假设是，IRS代表了一类新的药物，对肿瘤和胶质瘤的内皮间质成分都具有抗侵袭作用。因此，我们建议：目标1-确定IRS和细胞毒剂/辐射的组合是否在胶质瘤模型中导致显著的抗癌效应；目的2-测试IR的作用模式，因为它与一组胶质瘤启动细胞(GICs)中的GSK-3/β-连环蛋白/claudin-1信号通路有关；以及目标3-确定IR介导的胶质瘤微血管密度降低的细胞和生物学机制及其生理效应。

DESCRIPTION (provided by applicant): We seek to determine whether Indirubins (IRs), a class of chemicals with relative selective inhibitory activity against glycogen synthase kinase-3 (GSK-3), exhibit activity against malignant gliomas. These tumors remain amongst the most formidable cancers to treat, particularly due to their propensity to invade and infiltrate into normal brain. Based on data showing reduced glioma motility in vitro using lithium, a GSK-3 inhibitor that is FDA-approved for the treatment of bipolar disorders, we have initiated a bi-institutional phase 2 clinical trial, where lithium is added to standard cytotoxic therapy in patiets with newly diagnosed malignant glioma, to determine whether it will reduce glioma invasion. However, lithium has a narrow therapeutic index and its inhibitory activity for GSK-3 is not as specific. We thus have screened other GSK-3 inhibitors and discovered that the IRs are more potent than lithium and appear to be well tolerated in mice models of gliomas. Our pilot data shows that IRs: : a- inhibit glycogen synthase kinase- 3 (GSK-3) activity more potently than lithium; b- lead to the translocation of ¿-catenin from the membrane to the nucleus; c- change the expression of several ¿-catenin responsive genes related to cell-cell adhesion and invasion, including claudin-1, d-significantly reduce invasion of glioma cells both in vitro and in vivo; e- reduce the number of microvessels in gliomas; and f- reduce endothelial motility, at least in vitro. IR treatment significantly increases the survival of animals with orthotopic glioma and reduces the volume of ectopic flank gliomas. We thus propose to further study IRs in order to provide preclinical data related to their efficacy and toxicity and to understand their mechanism of action in glioma initiating cells (GICs) rather than cell lines. Our overall hypothesis is that IRs represent a novel class of agents with anti-invasive action for both the tumor and endothelial stromal components of the gliomas. We thus propose to: Aim 1-Determine whether the combination of IRs and cytotoxic agents/radiation leads to a significant anticancer effect in glioma models; Aim 2- Test IR's mode of action, as it relates to a GSK-3/¿-catenin/claudin-1 signaling pathway, in a panel of glioma initiating cells (GICs); and Aim 3- Determine the cellular and biologic mechanisms responsible for IR-mediated reduction of glioma microvessel density and their physiological effects.