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科学家或开发出新型膀胱癌的个体化疗法

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一篇发表于国际杂志PLoS One上的研究论文中,来自加州大学戴维斯分校(UC Davis)的科学家同杰克逊实验室的科学家们联合开发出了一种针对恶性膀胱癌的新型个体化疗法;在早期的概念验证研究中,研究者就对来自患者机体的膀胱肿瘤进行研究鉴别出了特殊的基因突变,随后他们将肿瘤移植入小鼠体内,基于前期研究,研究者利用肿瘤模型检测了多种疗法的有效性,最终证实了其中一种方法在小鼠和患者机体内同样有效。

  一篇发表于国际杂志PLoS One上的研究论文中,来自加州大学戴维斯分校(UC Davis)的科学家同杰克逊实验室的科学家们联合开发出了一种针对恶性膀胱癌的新型个体化疗法;在早期的概念验证研究中,研究者就对来自患者机体的膀胱肿瘤进行研究鉴别出了特殊的基因突变,随后他们将肿瘤移植入小鼠体内,基于前期研究,研究者利用肿瘤模型检测了多种疗法的有效性,最终证实了其中一种方法在小鼠和患者机体内同样有效。
  肿瘤学家Chong-Xian Pan表示,通过进行初筛,我们确定了可以发挥作用的疗法,从而就为患者是否获益提供了较大的机会,文章中我们开发的新型疗法可以减少毒性、增加作用效率并且降低患者的花费。从理论上来讲寻找到肿瘤的基因突变就会后期开发明确的疗法奠定了基础,比如利用靶向性药物来匹配遗传突变,然而当前尽管遗传学工具可以寻找到基因突变,其也并不能鉴别出哪些基因引发患者患癌。
  纵览癌症中所拥有的多种突变,即从引发儿童癌症的几十个基因突变到引发成年人患癌的成千上百个癌症,我们都会发现,肺癌或许拥有成百上千个突变,然而仅有一些突变是非常重要的,但基于这一点而言我们并不能确定哪些突变是重要的哪些是不重要的。抛开对癌症发生重要的基因突变不讲,肿瘤学家必须选择一种治疗手段来对患者进行治疗,如果选择错误,那么时间和毒性将会给患者带来巨大的影响。
  研究者Ralph de Vere White指出,我们会对病人机体的标本进行活组织检查,对其进行基因组分析来揭示肿瘤异常,如今我们只能猜想哪些突变可能诱发癌症,然而成功率仅有12%;尽管本文研究规模偏小,但其的确可以有效治疗膀胱癌,因为肿瘤在小鼠机体中可以快速发展,因此就可以帮助我们确定疗法是否是有效的,当然研究者还必须进行多种活组织样本的检测来追踪肿瘤的进化,寻找逃脱的基因突变并且检测新型的治疗方法。
  从某种角度来讲,药物顺铂并不能有效作用,而且吉西他滨也很少发挥作用,但将两种药物进行结合就可以帮助抑制小鼠机体中膀胱癌肿瘤的发展。研究者表示,利用移植病人的肿瘤进行后期研究或可帮助研究者选择最佳的疗法来治疗癌症患者。研究者希望利用癌症患者机体的活组织样本进行研究,对其进行测序并利用计算机程序对其进行结果分析最终确定哪种疗法可以有效抑制癌症的发展。(转化医学网360zhyx.com)
  以上为转化医学网原创翻译整理,转载请注明出处和链接!
转化医学网推荐的原文摘要:

Development and Characterization of Bladder Cancer Patient-Derived Xenografts for Molecularly Guided Targeted Therapy
PLoS ONE    DOI: 10.1371/journal.pone.0134346
Chong-xian Pan  , Hongyong Zhang , Clifford G. Tepper , Tzu-yin Lin, Ryan R. Davis, James Keck, Paramita M. Ghosh, Parkash Gill, Susan Airhart, Carol Bult, David R. Gandara, Edison Liu, Ralph W. de Vere White 
Background
The overarching goal of this project is to establish a patient-derived bladder cancer xenograft (PDX) platform, annotated with deep sequencing and patient clinical information, to accelerate the development of new treatment options for bladder cancer patients. Herein, we describe the creation, initial characterization and use of the platform for this purpose.
Methods and Findings
Twenty-two PDXs with annotated clinical information were established from uncultured unselected clinical bladder cancer specimens in immunodeficient NSG mice. The morphological fidelity was maintained in PDXs. Whole exome sequencing revealed that PDXs and parental patient cancers shared 92–97% of genetic aberrations, including multiple druggable targets. For drug repurposing, an EGFR/HER2 dual inhibitor lapatinib was effective in PDX BL0440 (progression-free survival or PFS of 25.4 days versus 18.4 days in the control, p = 0.007), but not in PDX BL0269 (12 days versus 13 days in the control, p = 0.16) although both expressed HER2. To screen for the most effective MTT, we evaluated three drugs (lapatinib, ponatinib, and BEZ235) matched with aberrations in PDX BL0269; but only a PIK3CA inhibitor BEZ235 was effective (p<0.0001). To study the mechanisms of secondary resistance, a fibroblast growth factor receptor 3 inhibitor BGJ398 prolonged PFS of PDX BL0293 from 9.5 days of the control to 18.5 days (p<0.0001), and serial biopsies revealed that the MAPK/ERK and PIK3CA-AKT pathways were activated upon resistance. Inhibition of these pathways significantly prolonged PFS from 12 day of the control to 22 days (p = 0.001). To screen for effective chemotherapeutic drugs, four of the first six PDXs were sensitive to the cisplatin/gemcitabine combination, and chemoresistance to one drug could be overcome by the other drug.
Conclusion
The PDX models described here show good correlation with the patient at the genomic level and known patient response to treatment. This supports further evaluation of the PDXs for their ability to accurately predict a patient’s response to new targeted and combination strategies for bladder cancer.

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