Title: 應用新穎的基因轉殖小鼠模式以研究肺癌形成的分子機制與其標靶治療
Characterization of Lung Tumorigenesis in Genetically Engineered Mouse Models of Lung Cancer
Authors: 梁美智
Liang Mei-Chih
Keywords: 非小細胞肺癌;上皮生長因子受體;基因突變;基因轉殖小鼠;標靶治療;抗藥性;細胞凋亡;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
Issue Date: 2012
Abstract: 肺癌是臺灣地區十大癌症死因的首位,而其中百分之八十五的患者是屬於非小細胞肺癌。統計顯示每年國人約有近八千人死於肺癌。所以對非小細胞肺癌分子病理機制的進一步的研究,以期有效治療肺癌,並降低死亡率,實在是當務之急。近年來醫學的發展,已開發出肺癌標靶藥物,可以針對帶有特定基因型突變的非小細胞肺癌患者,給與客製化的標靶療程設計。例如,高比例的國人肺腺癌患者中,其上皮生長因子受體(EGFR),有過度表現或突變的情形。而針對這個特定目標設計的標靶藥物,如erlotinib和gefitinib,也已經使用於臨床治療。然而,部分帶有EGFR基因突變的肺腺癌患者,並無法以標靶藥物有效治療與控制病情。推測其原因,有可能是這些患者除了EGFR基因異常外,另外還帶有其他的基因突變。這些被列入考慮的突變基因中,包括著名的抗細胞凋亡基因BCL-2。 高度表現的BCL-2蛋白質,已在包括肺癌等多種癌症檢體與癌症細胞株中被檢測到。然而BCL-2在肺癌中所扮演的角色,目前還有許多待解與不明瞭的地方。本計畫將同時以帶有人類BCL-2與人類突變上皮生長因子受體 (包括肺腺癌患者中常見的突變EGFR L858R或抗藥性突變EGFR T790M-L858R) 的基因轉殖小鼠為模式動物,誘導轉殖基因在小鼠肺部過度表現,以研究BCL-2在EGFR突變型肺癌的形成、EGFR標靶治療、與抗藥性中所扮演的角色。同時,本研究將探討比較BCL-2的大量表現與否,是否會影響非小細胞肺癌小鼠的存活率、其肺癌嚴重程度、和其癌細胞的增生與凋亡。本研究同時也將針對因為BCL-2突變,而可能過度活化的癌症相關分子訊息傳遞路徑,試驗阻抗BCL-2活性的標靶療法的可行性。本計畫的成果,將有助於我們進一步了解非小細胞肺癌形成的分子機制,進而設計出更有效的治療方式,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.
Gov't Doc #: NSC101-2320-B009-003-MY2
URI: http://hdl.handle.net/11536/98710
Appears in Collections:Research Plans