项目来源

台湾省政府科研基金(GRB)

项目主持人

赵婷婷

项目受资助机构

台湾省天主教耕莘医院医学研究中心

项目编号

NSC102-2314-B567-001-MY2

财政年度

2014,2013

立项时间

未公开

项目级别

省级

研究期限

未知 / 未知

受资助金额

2200.00千元台币

学科

基础医学；临床医学；生物技术(医)

学科代码

未公开

基金类别

商品化/学术补助

关键词

非小细胞肺癌 ; 磷酸酶2A癌性抑制因子 ; 得舒缓 ; 新一代标靶药afatinib(BIBW2992) ; 得舒缓衍生物(TD2-2) ; non-small-cell lung carcinoma ; Cancerous inhibitor of protein phosphatase 2A(CIP2A) ; Tarceva ; afatinib(BIBW2992) ; TD2-2

参与者

王诚一；陈昆锋；林恒毅

参与机构

未公开

项目标书摘要：目前肺癌为最常见的恶性肿瘤之一，肺癌约有70%族群属於「非小细胞肺癌」,每年约有150万个新生病例，其占癌症诊断病例12%。截至目前肺癌治疗虽已有很大的进展，但其预後仍差，五年存活率低於15%左右。因此，极需发展新型且更具效果的治疗方法。时至今曰，标靶疗法的药物问世之後，部份肺腺癌患者的治疗成果呈现曙光。对於特定的病患，主要是所谓病患肿瘤本身具有「靶心」,系指上皮细胞生长因子接受器(EGFR),如果此一基因发生变异，就代表这肿瘤具有「靶心」,很容易被标靶治疗的化学药物击中靶心，而这类具有靶心的肺癌患者平均有七成左右接受化疗之後会有显着效果。相较於传统疗法，标靶疗法有较少的副作用。但是对於没有EGFR变异的病人，也就是野生型EGFR的肺癌患者，目前仍是没有合适的标靶疗法的药物。石粦酸酶2A癌性抑制因子(Cancerous inhibitor of PP2A,CIP2A)为近年来被证实的一种新型致癌因子，能透过抑制PP2A对c-Myc的去磷酸化作用来阻止c-Myc蛋白降解，进而达到稳定c-Myc表现与促进细胞增殖及促进非贴附性生长与肿瘤形成作用等功能。CIP2A在许多人类恶性肿瘤中过度表达与预後不良有关。目前有关CIP2A在肺癌中之功能方面研究与分子调控机制尚未被阐释清楚。其是否能成为肺癌治疗标靶仍有待更深入探讨。Erlotinib(Tarceva,得舒缓)是上皮细胞生长因素因子—赂氨酸激酶拮抗剂(EGFR-TKI),用於有EGFR突变非小细胞肺癌患者的标靶治疗药物，然而我们团队发现,erlotinib有新的机转，可以透过CIP2A,对於没有EGFR变异，也就是野生型EGFR的肺癌细胞株，也有抑制癌细胞的效果，我们进一步合成有更强CIP2A抑制效果的衍生物，此外我们也发现新一代标靶药afatinib(BIBW2992)对於CIP2A也有良好的抑制效果。本计昼旨在探索erlotinib其衍生物(TD2-2)与新一代标靶药afatinib等作用，於非小细胞肺癌细胞株探讨其抑制癌细胞生长与诱发细胞凋亡之分子机制调控。其生长抑制与细胞凋亡功能起因於CIP2A受到药物抑制进而影响PP2A活性，进而导致下游Akt磷酸化受到抑制所致，尤以得舒缓衍生物TD2-2与afatinib效果最为显着。另研究中利用短干扰RNA(siRNA)策略抑制CIP2A表现，於这些小分子化合物作用下能更显着加强肺癌细胞的凋亡与促进PP2A的活性。更进一步在裸鼠异位移植肿瘤治疗模式进行体内实验我们亦观察到相同现象。根据初步实验结果显示，这些化合物透过转录调节抑制CIP2A 蛋白并促进PP2A的活性进而调节Akt讯息传递达到抑制肺癌细胞生长与诱导细胞凋亡作用。总而言之，根据我们的初步结果，在肺癌中CIP2A蛋白不失为一个有潜力新型标靶，且afatinib与得舒缓衍生物(TD2-2)两化合物亦皆能透过有效抑制CIP2A蛋白来作用。如此调控机制，不失为有别於上皮细胞生长因素因子—酪胺酸酶抑制作用的一种更具潜力新型肺癌治疗药。

Application Abstract: Lung cancer has already been the first cause of the death of cancer in the whole world at present.Each year nearly 1.5 million people are diagnosed with lung cancer,accounting for about 12%of total cancer diagnosed.Because of 70%population in the firstly diagnosis are the non-small-cell lung carcinoma(NSCLC)occurs when it has already local extension or distant metastases.Lung cacner has become the major human health risk.Although there are some improvements in lung cancer therapies,the prognosis is poor and hardly be cured with the five-year survival rate.It is importantly highlight the urgent need for identification of novel molecular targets for lung cancer chemotherapy.Nowadays,target therapies bring new hope to partial lung cancer patients.Patients with certain EGFR mutations have a higher response rate to an EGFR targeted drug,such as gefitinib(Iressa)and erlotinib(Tarceva).Besides,target therapies with little or minor side effects may compensate for the incompleteness of conventional chemotherapies.However,there are still no effective target therapies for EGFR-wild type NSCLC.Cancerous inhibitor of protein phosphatase 2A(CIP2A)is a recently identified oncoprotein that can stabilize c-Myc protein,and promote in vitro anchorage-independent cell proliferation and in vivo tumor formation.It has been found that CIP2A is overexpressed in several cancers which associated with prognosis.So far,the function of CIP2A and related signaling regulation for lung cancer are still ambiguously.However,the molecular mechanisms underlying the role of CIP2A need to investigation or whether CIP2A can serve as a new drug target need to be determined in lung cancer.Originally,erlotinib is used as EGFR Tyrosine kinase inhibitor(TKI)for EGFR mutation NSCLC patients.Our team found it has new mechanism as CIP2A inhibitor and can work on wild-type EGFR NSCLC cell lines.Furthermore,we synthesis erlotinib derivatives with better effect on CIP2A.We also found new generation TKI,afatinib(BIBW2992),have stronger effect on CIP2A.In this project,we explore the mechanism of apoptosis induction following by erlotinib,erlotinib derivative(TD2-2)or afatinib.The tumor growth inhibition and apoptosis induction cause of CIP2A inhibited by these drugs.In NSCLC cell line,the CIP2A mediates the apoptotic from active PP2A and down regulated phosph-Akt through the afatinib and TD2-2,significantly.Moreover,silencing CIP2A by siRNA inhibited the proliferation and oncogenic activity and potentiated PP2A activity of lung cancer cells.Eventually,the xenograft tumor model demonstrated the tumor growth inhibitory and PP2A activity enhancement following TD2-2 and afatinib treat.Basing on our results,these compounds could modulate CIP2A expression and PP2A activity by regulation of CIP2A transcriptional activity,which had the ability to inhibit proliferation and induce apoptosis in NSCLC cells.Furthermore,the compounds could induce the down-regulation of CIP2A protein and suppressed CIP2A-Akt pathway.Moreover,these drugs demonstrate significantly anticancer potential in vitro and in vivo.Our preliminary data show that CIP2A will be a potential target for NSCLC therapy.These chemical compounds,TD2-2 or afatinib,exhibit potential for lung cancer chemotherapy via CIP2A reduction.

项目受资助省

台湾省