Mol Cancer Ther：研究证实小分子药物CFAK-Y15可有效治疗脑癌

日前，罗斯威尔癌症中心（RPCI）的研究者们在Molecular Cancer Therapeutics杂志上发表了一项有关评价一种小分子抑制剂CFAK-Y15在治疗脑癌效果方面的临床前研究结果。，首次论证了用CFAK-Y15抑制黏着斑激酶（FAK）蛋白是一个调控胶质母细胞瘤细胞生长的有效途径，尤其是与标准化疗剂替莫唑胺联用。

FAK在肿瘤细胞中过量表达，并且已经显示出在癌细胞的生存中起关键作用。CFAK-Y15通过FAK蛋白上自身磷酸化位点的上游靶点来产生对FAK激酶的特异性抑制。它属于同时也通过抑制自身磷酸化的方式抑制了肿瘤蛋白Src的这种“二合一”的类别。

“我们发现，CFAK-Y15显着降低了胶质母细胞瘤细胞的生存能力，并且在很多情况下似乎引起肿块的缩小—尤其是当CFAK-Y15与替莫唑胺发生了结合。”这篇论文的一作Golubovskaya博士记录到。

“是它们合成了那些对于癌细胞和肿瘤干细胞，尤其是在入侵和转移癌的生存调控方面很关键的FAK的靶向信号。”“我们期盼着看到这项研究能够转化到临床阶段，以满足对胶质母细胞瘤更有效治疗的巨大需求，”美国外科医师学会会员，首席外科医生兼肿瘤外科部门主席，资深作者William G. Cance博士记录到。

“它的潜在影响是巨大的，因为胶质母细胞瘤是一个如此具侵略性的肿瘤，并且因为我们知道它们是在特别大量的产生FAK。”“我们发现，CFAK-Y15显着降低了胶质母细胞瘤细胞的生存能力，并且在很多情况下似乎引起肿块的缩小—尤其是当CFAK-Y15与替莫唑胺发生了结合。”这篇论文的一作Golubovskaya博士记录到。“它的潜在影响是巨大的，因为胶质母细胞瘤是一个如此具侵略性的肿瘤，并且因为我们知道它们是在特别大量的产生FAK。”

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Pharmacological blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide
ABSTRACT
Malignant gliomas are characterized by aggressive tumor growth with a mean survival of 15-18 months and frequently developed resistance to temozolomide. Therefore, strategies that sensitize glioma cells to temozolomide have a high translational impact. We have studied focal adhesion kinase (FAK), a tyrosine kinase and emerging therapeutic target that is known to be highly expressed and activated in glioma. In this report we tested the FAK autophosphorylation inhibitor, Y15 in DBTRG and U87 glioblastoma cells. Y15 significantly decreased viability and clonogenicity in a dose-dependent manner, increased detachment in a dose and time-dependent manner, caused apoptosis and inhibited cell invasion in both cell lines. In addition, Y15 treatment decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Administration of Y15 significantly decreased subcutaneous DBTRG tumor growth with decreased Y397-FAK autophosphorylation, activated caspase-3 and PARP. Y15 was administered in an orthotopic glioma model, leading to an increase in mouse survival. The combination of Y15 with temozolomide was more effective than either agent alone in decreasing viability and activating caspase-8 in DBTRG and U87 cells in vitro. In addition, the combination of Y15 and temozolomide synergistically blocked U87 brain tumor growth in vivo. Thus, pharmacologic blockade of FAK autophosphorylation with the oral administration of a small molecule inhibitor Y15 has a potential to be an effective therapy approach for glioblastoma either alone or in combination with chemotherapy agents such as temozolomide.

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