Investigating drug targets and improving drug delivery for anti-cancer treatment of osteosarcoma

研究药物靶点并改善骨肉瘤抗癌治疗的药物输送

基本信息

  • 批准号:
    10379935
  • 负责人:
  • 金额:
    $ 39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Osteosarcoma is cancer of bone, most common in children and young adults. Metastasis is either present at the time of diagnosis or develops later during the course of treatment in most patients. The survival rate with metastatic osteosarcoma is very low, therefore new therapeutic interventions are needed. Our lab has demonstrated that Riluzole, a glutamate release inhibitor, is effective in inhibiting proliferation and inducing apoptosis both in human and mouse osteosarcoma. Furthermore, we have demonstrated that Riluzole blocks the activity of the mGluR5 receptor signaling to inhibit growth in osteosarcoma cells. Yes associated protein (YAP) is a transcription co-activator involved in cell proliferation. The evidence in literature shows that YAP phosphorylated at serine 127 facilitates cytoplasmic sequestration and degradation of YAP. Furthermore, YAP is phosphorylated at Y357 by C-Abl kinase under DNA damage-induced stress. Interestingly, phosphorylation of YAP at Y357 promotes strong interaction with p73, a transcription co-activator, to induce transcription of pro- apoptotic genes. Our data has shown that Riluzole decreased phosphorylation of YAP at serine 127 and increased nuclear localization of YAP. Furthermore, Riluzole also changed the localization of a YAP mutant, YAPS5A (five serine residues at 61, 109, 127, 164, and 397 changed to alanine) from cytoplasm to nucleus suggesting that change is localization is independent of phosphorylation at these sites. We hypothesize that the increase in nuclear localization of YAP facilitates transcription of pro-apoptotic genes. We want to determine if YAP is directly involved in Riluzole-induced apoptosis and if YAP is regulated by C-Abl to activate pro-apoptotic genes in osteosarcoma cells. We will use human metastatic osteosarcoma cells, LM7, and mouse cells lines, OS482, to study the effect of: a) Riluzole on phosphorylation of YAP at Y357 b) C-Abl inhibitors on phosphorylation of YAP at Y357 and Riluzole-induced apoptosis c) Riluzole on osteosarcoma cells with YAP knockdown or C-Abl knockdown to confirm the role of YAP and C-Abl in apoptosis d) Riluzole on YAP and P73 binding and on transcription of Bax promoter in a luciferase reporter assay. Our recent in vitro data has demonstrated that Riluzole released from the iron oxide nanocage is more effective in inducing apoptosis in LM7 cells compared to free Riluzole or Riluzole released from the nanosphere. We hypothesize that Riluzole released from Riluzole-loaded nanocage will be more effective, compared to free Riluzole, in reducing metastasis in a nude mouse model. We will implant osteosarcoma cells, LM7.eGFP.ffLuc, in the tail vein of nude mouse. We will randomly sort the animals in 4 groups and carry out the following treatments. 1) no treatment, 2) free Riluzole, 3) nanocage alone, 4) Riluzole-loaded nanocage. We will treat the animals and monitor metastasis using bioluminescence imaging in all groups. We will perform whole animal magnetic resonance imaging (MRI) for biodistribution of iron oxide nanocage carriers and then use quantitative susceptibility mapping (QSM) to quantify the concentration of iron oxide nanocages at metastasis sites. Our data has demonstrated that glutamate signaling via mGluR5 is important in colony forming ability of LM7 cells. In Aim 3, we will assess the efficiency of mGluR5 siRNA delivery to decrease tumor size in a xenograft mouse model. We will use mGluR5 siRNA-loaded iron oxide nanocage and induce siRNA release using magnetic hyperthermia in mice. We will perform whole animal MRI/QSM and ex vivo MRI/QSM to determine the nanocage concentration in each organ and tumor site. We will perform and analyze the experiments in Aim 2 and Aim 3 in collaboration with my colleague, Dr. Hiroshi Matsui, who is an expert in bionanotechnology. In brief, we expect to: a) demonstrate a direct role of YAP in Riluzole-induced apoptosis of osteosarcoma cells b) assess the efficacy of the delivery method of Riluzole in preventing metastasis in xenograft nude mouse model c) deliver mGluR5 siRNA via nanoparticle to prevent tumor establishment in a xenograft mouse model. Riluzole is used as a FDA approved therapeutic drug for Amyotrophic Lateral Sclerosis (ALS). This study is a drug- repurposing study in which Riluzole is used as an anti-cancer agent for osteosarcoma. !
骨肉瘤是骨癌,最常见于儿童和年轻人。转移要么存在于 在大多数患者中,诊断时间或治疗过程中的后期发展。存活率与 骨肉瘤的转移性非常低,因此需要新的治疗干预。我们的实验室 证明了谷氨酸释放抑制剂阿曲唑在抑制增殖和诱导增殖中是有效的。 人和小鼠骨肉瘤细胞凋亡。此外,我们已经证明,阿舒唑阻断 mGluR 5受体信号传导抑制骨肉瘤细胞生长的活性。Yes相关蛋白 (YAP)是参与细胞增殖的转录辅激活因子。文献证据表明,雅普 在丝氨酸127处磷酸化促进雅普的细胞质螯合和降解。此外,雅普 在DNA损伤诱导的应激下,被C-Abl激酶在Y357处磷酸化。有趣的是, 在Y357处的雅普促进与转录共激活因子p73的强相互作用,以诱导前- 凋亡基因我们的数据表明,阿曲唑降低了雅普在丝氨酸127位的磷酸化, 增加雅普的核定位。此外,阿曲唑还改变了雅普突变体的定位, YAPS 5A(61、109、127、164和397处的5个丝氨酸残基变为丙氨酸)从细胞质到细胞核 这表明变化是定位的,不依赖于这些位点的磷酸化。我们假设 雅普核定位的增加促进促凋亡基因的转录。我们想 确定雅普是否直接参与阿曲唑诱导的细胞凋亡,以及雅普是否受C-Abl调节以激活 骨肉瘤细胞中的促凋亡基因。我们将使用人转移性骨肉瘤细胞LM 7, 小鼠细胞系OS 482,以研究:a)阿曲唑对雅普在Y357处磷酸化的影响B)C-Abl 雅普在Y357处磷酸化和阿曲唑诱导的细胞凋亡的抑制剂c)阿曲唑对骨肉瘤的作用 用雅普敲低或C-Abl敲低的细胞证实雅普和C-Abl在细胞凋亡中的作用 对雅普和P73结合以及对荧光素酶报告基因测定中Bax启动子转录的影响。 我们最近的体外数据表明,从氧化铁纳米笼中释放的阿珠唑比从纳米笼中释放的阿珠唑更多。 与游离的阿珠唑或从LM 7细胞释放的阿珠唑相比, 纳米球我们假设从载有阿舒唑的纳米笼中释放的阿舒唑将更有效, 与游离阿曲唑相比,在裸鼠模型中减少转移。我们会植入骨肉瘤细胞, LM7.eGFP. ffLuc,裸鼠尾静脉。我们将动物随机分为4组, 以下治疗。1)无处理,2)游离的阿珠唑,3)单独的纳米笼,4)负载阿珠唑的纳米笼。 我们将治疗动物并在所有组中使用生物发光成像监测转移。我们将执行 用于氧化铁纳米笼载体的生物分布的整个动物磁共振成像(MRI),然后 使用定量磁化率映射(QSM)来量化氧化铁纳米笼在 转移部位。 我们的数据表明,通过mGluR 5的谷氨酸信号传导在LM 7的集落形成能力中是重要的 细胞在目标3中,我们将评估mGluR 5 siRNA递送在异种移植物中减小肿瘤大小的效率 小鼠模型我们将使用载有mGluR 5 siRNA的氧化铁纳米笼,并使用 小鼠的磁热疗。我们将进行全动物MRI/QSM和离体MRI/QSM,以确定 每个器官和肿瘤部位的纳米笼浓度。我们将在Aim中执行和分析实验 2和目标3与我的同事,松井博士,谁是生物纳米技术的专家合作。 简而言之,我们希望:a)证明雅普在阿珠唑诱导的骨肉瘤细胞凋亡中的直接作用 B)评估阿曲唑的递送方法在异种移植裸鼠中预防转移的功效 模型c)通过纳米颗粒递送mGluR 5 siRNA以防止异种移植小鼠模型中的肿瘤建立。 阿曲唑被用作FDA批准的肌萎缩侧索硬化症(ALS)的治疗药物。本研究是一项 药物再利用研究,其中阿曲唑被用作骨肉瘤的抗癌剂。 !

项目成果

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Shahana Sultana Mahajan其他文献

Shahana Sultana Mahajan的其他文献

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{{ truncateString('Shahana Sultana Mahajan', 18)}}的其他基金

Investigating drug targets and improving drug delivery for anti-cancer treatment of osteosarcoma
研究药物靶点并改善骨肉瘤抗癌治疗的药物输送
  • 批准号:
    10599098
  • 财政年份:
    2020
  • 资助金额:
    $ 39万
  • 项目类别:

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