應用基因剔除的小鼠模式研究小細胞肺癌形成的分子機制

Abstract

肺癌是臺灣地區十大癌症死因的首位，而其中小細胞肺癌約佔所有肺癌的百分之十五。統計顯示小細胞肺癌是造成死亡率最高的肺癌，患者五年平均存活率只有百分之五。而近年來流行於非小細胞肺癌的標靶療法，也並不適用於小細胞肺癌的治療。所以對癌症分子機制的進一步的研究，以期有效醫治小細胞肺癌，並降低死亡率，實在是當務之急。因為癌症抑制基因(tumor suppressor gene)突變而造成的基因缺失，已在包括肺癌等多種癌症中被發現。例如在小細胞肺癌中，約有百分之九十的患者，同時帶有二種癌症抑制基因p53和Rb的突變。從動物實驗中也已證實，若在肺部去活化這二種基因，可以使小鼠長出小細胞肺癌。另外一個對調控細胞生存與生長很重要的癌症抑制基因PTEN的基因突變，則也在約百分之十的小細胞肺癌患者與細胞株中被鑑定出來。然而究竟PTEN基因缺陷，會對小細胞肺癌的形成有何重大影響，直到目前還有許多不清楚的地方。本計畫主要目的，是將利用帶有肺癌的小鼠做為模式動物，探討PTEN在小細胞肺癌形成的過程中，其所扮演的角色。本研究將創造出一種新的基因工程改造小鼠，其肺部同時帶有三種癌症抑制基因缺失，包括PTEN、p53、和Rb。控制組則包括了肺部同時帶有p53和Rb缺失的小細胞肺癌模式小鼠。本實驗將探討比較PTEN的存在與否，會不會影響小細胞肺癌小鼠的存活率、肺癌嚴重程度、癌細胞增生與凋亡。本研究同時也將針對，因為PTEN缺失而可能過度活化的癌症相關分子路徑，設計標靶療法來抑制其活性。以期進一步了解，標靶藥物是否有效用來治療帶有不活化PTEN的小細胞肺癌。本研究的成果，將有助於我們對於小細胞肺癌形成分子機制的了解，進而設計出更有效的治療方式，以提高患者存活率。

In Taiwan, lung cancer is the leading cause of cancer-related deaths. The histological subgroup small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. SLCL is one of the most devastating lethal tumor types with a five-year survival of less than 5%. Therefore, there is an emergency need for developing more effective therapeutics against SCLCs. Aberrations of tumor suppressor genes (TSGs) have been found in SCLCs and may serve as a promising target for new cancer treatment designs. For example, loss of the TSG PTEN allele has been identified in ~10% of SCLCs. The PTEN inactivation is associated with aberrant cell survival and growth by activating the AKT signaling and downstream pathways. However, the molecular mechanism by which PTEN loss may contribute to lung tumorigenesis and drug resistance is still waited to be elucidated. In this grant proposal, we will investigate the role of PTEN in the development of SCLC using a novel triple p53/Rb/PTEN conditional knockout mouse line in which the lung tumors are driven by lung-specific inactivation of the p53 and Rb alleles. Moreover, we will examine whether agents targeting the PI3K and/or mTOR may have a therapeutic effect in lung tumors in the triple conditional knockout mice. Results from this study may deepen our understanding of SCLC tumorigenesis and may have an impact in developing new therapeutic strategies.