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

描述（由申请人提供）：我们试图确定靛玉红（IR），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，是否对恶性神经胶质瘤具有活性。这些肿瘤仍然是最难治疗的癌症之一，特别是由于它们倾向于侵入和渗透到正常大脑中。基于显示使用锂（一种GSK-3抑制剂，FDA批准用于治疗双相情感障碍）在体外降低胶质瘤运动性的数据，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中，将锂添加到标准细胞毒性治疗中，以确定它是否会减少胶质瘤侵袭。然而，锂具有窄的治疗指数，并且其对GSK-3的抑制活性没有那么特异性。因此，我们筛选了其他GSK-3抑制剂，发现IR比锂更有效，并且在胶质瘤小鼠模型中耐受性良好。我们的试验数据表明，IR：a-抑制糖原合成酶激酶-3（GSK-3）的活性比锂更有效; B-导致<$-连环蛋白从膜易位到细胞核; c-改变几种细胞因子的表达， 与细胞-细胞粘附和侵袭相关的β-连环蛋白应答基因，包括claudin-1，d-β，在体外和体内均显著降低胶质瘤细胞的侵袭。 体内; e-减少胶质瘤中的微血管数量;和f-至少在体外减少内皮运动。IR治疗显著增加了原位胶质瘤动物的存活率，并减少了异位侧腹胶质瘤的体积。因此，我们建议进一步研究IR，以提供与其疗效和毒性相关的临床前数据，并了解其在胶质瘤起始细胞（GIC）而不是细胞系中的作用机制。我们的总体假设是，IR代表了一类新的药物，对胶质瘤的肿瘤和内皮基质成分都具有抗侵袭作用。因此，我们建议：目标2-测试IR的作用模式，因为它涉及一组胶质瘤起始细胞（GIC）中的GSK-3/β-连环蛋白/密蛋白-1信号传导途径;以及 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.