标题: | 应用新颖的基因转殖小鼠模式以研究肺癌形成的分子机制与其标靶治疗 Characterization of Lung Tumorigenesis in Genetically Engineered Mouse Models of Lung Cancer |
作者: | 梁美智 Liang Mei-Chih 国立交通大学生物科技学系(所) |
关键字: | 非小细胞肺癌;上皮生长因子受体;基因突变;基因转殖小鼠;标靶治疗;抗药性;细胞凋亡;non-small cell lung cancer;genetically engineered mouse model;epidermal growth factor receptor (EGFR);targeted therapy;acquired resistance;B-cell lymphoma 2 (BCL-2);apoptosis |
公开日期: | 2012 |
摘要: | 肺癌是台湾地区十大癌症死因的首位,而其中百分之八十五的患者是属于非小细胞肺癌。统计显示每年国人约有近八千人死于肺癌。所以对非小细胞肺癌分子病理机制的进一步的研究,以期有效治疗肺癌,并降低死亡率,实在是当务之急。近年来医学的发展,已开发出肺癌标靶药物,可以针对带有特定基因型突变的非小细胞肺癌患者,给与客制化的标靶疗程设计。例如,高比例的国人肺腺癌患者中,其上皮生长因子受体(EGFR),有过度表现或突变的情形。而针对这个特定目标设计的标靶药物,如erlotinib和gefitinib,也已经使用于临床治疗。然而,部分带有EGFR基因突变的肺腺癌患者,并无法以标靶药物有效治疗与控制病情。推测其原因,有可能是这些患者除了EGFR基因异常外,另外还带有其他的基因突变。这些被列入考虑的突变基因中,包括着名的抗细胞凋亡基因BCL-2。 高度表现的BCL-2蛋白质,已在包括肺癌等多种癌症检体与癌症细胞株中被检测到。然而BCL-2在肺癌中所扮演的角色,目前还有许多待解与不明瞭的地方。本计画将同时以带有人类BCL-2与人类突变上皮生长因子受体 (包括肺腺癌患者中常见的突变EGFR L858R或抗药性突变EGFR T790M-L858R) 的基因转殖小鼠为模式动物,诱导转殖基因在小鼠肺部过度表现,以研究BCL-2在EGFR突变型肺癌的形成、EGFR标靶治疗、与抗药性中所扮演的角色。同时,本研究将探讨比较BCL-2的大量表现与否,是否会影响非小细胞肺癌小鼠的存活率、其肺癌严重程度、和其癌细胞的增生与凋亡。本研究同时也将针对因为BCL-2突变,而可能过度活化的癌症相关分子讯息传递路径,试验阻抗BCL-2活性的标靶疗法的可行性。本计画的成果,将有助于我们进一步了解非小细胞肺癌形成的分子机制,进而设计出更有效的治疗方式,以期提高患者的存活率。 Lung cancer is the leading cause of cancer related deaths in Taiwan. Genetic aberrations in critical pathways mediating cell proliferation, survival, and apoptosis, have been linked to lung tumoregenesis. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are in clinical use for treating lung cancer patients harboring epidermal growth factor receptor (EGFR) kinase domain mutations. Despite recent progress in targeted therapy studies, it reminds an unsolved question that approximately 25% of lung cancer patients harboring EGFR active domain mutations had poor response to TKIs gefitinib or erlotinib. Moreover, approximately 30% of TKI acquired resistance cases was not associated with EGFR mutations in T790M or the c-met amplifications. It seems likely that the initial resistance and/or acquired resistance to TKIs may be associated with unidentified alterations in signaling pathways that direct the EGFR signaling to drug induced tumor cell death. Expression of the anti-apoptotic protein BCL-2 has been identified in approximately 35% of non-small cell lung cancer (NSCLC) in a meta-analysis. The molecular mechanisms by which BCL-2 may contribute to oncogenic EGFR-driven tumor development and targeted therapy response have not been elucidated in vivo. In this proposal, we will use genetically engineered mice harboring both the pre-survival hBCL-2 and the kinase domain mutation hEGFR, either the frequently altered L858R mutation or the erlotinib-resistant double mutant T790M-L858R, as a model system. We will investigate the impact of inducible hBCL-2 overexpression in lung tumors driven by the oncogenic hEGFR and examine selected downstream mediators involved in the EGFR and BCL-2 signaling pathways. Because the role of BCL-2 in anti-apoptosis, we will evaluate whether BCL-2 inhibition may sensitize lung tumors to EGFR TKIs. Results from these studies may be helpful for developing more effective (combination) targeted therapeutics based on our understanding of how BCL-2 mediates lung tumor development and EGFR TKI sensitivity. |
官方说明文件#: | NSC101-2320-B009-003-MY2 |
URI: | http://hdl.handle.net/11536/98710 https://www.grb.gov.tw/search/planDetail?id=2633792&docId=395863 |
显示于类别: | Research Plans |