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摘要
背景:目前尽管有包括手术、放疗、化疗和清髓造血干细胞救援等多项联合的治疗方法,但神经母细胞瘤(NB)仍约占所有儿童肿瘤的8%,占死亡人数的15%以上,总生存率很低。因此,努力加强研究以确定新的靶点和新的治疗方法,以提高这些儿童的治愈率。每年开发和评估许多新的药物,为恶性肿瘤的治疗提供了宝贵的资源,并用现有的药理学和毒理学数据的优势作为考虑对象。 方法:为了确定潜在的治疗靶点,我们从小分子库筛选了151个小分子激酶抑制剂对抗NB细胞株。基于我们的初步筛选数据,我们进一步研究了BCR-ABL靶向小分子抑制剂对NB细胞生长和存活的影响。 结果:目前可用的BCR-ABL抑制剂有多种活性,可能反映了每个组合分子的异质性和非靶点活性。在深入分析口服泊那替尼,多靶点激酶抑制剂和有效的药物治疗难治性费城染色体阳性白血病(PH),显示其在亚微摩尔浓度的生长抑制作用。此外,我们还发现这干扰胰岛素样生长因子-1受体(IGF-1R)潜在的信号通路和Src活性,能够抑制细胞的迁移和诱导细胞凋亡。 结论:我们的研究目标主要增长的调控途径,为泊那替尼治疗难治性NB早期阶段的临床试验及其深入研究提供实验基础。
关键词: 神经母细胞瘤,小分子激酶抑制剂,IGF-1受体,bcr-abl,肉瘤,泊那替尼
Current Cancer Drug Targets
Title:In Vitro Sensitivity Profiling of Neuroblastoma Cells Against A Comprehensive Small Molecule Kinase Inhibitor Library to Identify Agents for Future Therapeutic Studies
Volume: 17 Issue: 6
关键词: 神经母细胞瘤,小分子激酶抑制剂,IGF-1受体,bcr-abl,肉瘤,泊那替尼
摘要: Background: Neuroblastoma (NB) constitutes about 8% of all childhood tumors, yet accounts for more than 15% of deaths, with an unacceptable overall survival rate. These rates are despite the current multimodal therapeutic approaches involving surgery, radiation, chemotherapy and myeloablation with hematopoietic stem cell rescue. Hence, efforts have intensified to identify new targets and novel therapeutic approaches to improve cure rates in these children. Numerous new agents for adult malignancies are developed and evaluated for cancer each year, providing an invaluable resource, with the added advantage of available pharmacologic and toxicity data for consideration.
Methods: To identify potential therapeutic targets, we screened a small molecule library of 151 small kinase inhibitors against NB cell lines. Based on our initial screening data, we further examined the potential of Bcr-Abl targeting small molecule inhibitors to affect the growth and survival of NB cells. Results: There is diverse activity among the currently available Bcr-Abl inhibitors, possibly reflecting the molecular heterogeneity and off-target activity in each combination. In depth analyses of ponatinib, an oral multi-target kinase inhibitor and effective agent in the treatment of refractory Philadelphia chromosome (Ph) positive leukemia, show growth inhibition at sub-micromolar concentrations. In addition, we also identified the potential of this agent to interfere with insulin-like growth factor-1 receptor (IGF-1R) signaling pathways and Src activity, inhibit cell migration and induce apoptosis. Conclusion: Our findings provide initial data on ponatinib’s potential to target key growth regulatory pathways and provide the rationale for further studies and evaluation in future early phase clinical trials for the treatment of refractory NB.Export Options
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Cite this article as:
In Vitro Sensitivity Profiling of Neuroblastoma Cells Against A Comprehensive Small Molecule Kinase Inhibitor Library to Identify Agents for Future Therapeutic Studies, Current Cancer Drug Targets 2017; 17 (6) . https://dx.doi.org/10.2174/1568009617666161122145219
DOI https://dx.doi.org/10.2174/1568009617666161122145219 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
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Cancer remains one of the most challenging diseases, with its complexity and adaptability necessitating continuous research efforts into more effective and targeted therapeutic approaches. Recent years have witnessed significant progress in understanding the molecular and genetic basis of cancer, leading to the identification of novel drug targets. These include, but ...read more
Role of Immune and Genotoxic Response Biomarkers in Tumor Microenvironment in Cancer Diagnosis and Treatment
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process of exploring and investigating the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
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