Targeting TGF-beta Signaling in Lung Cancer

描述（由申请人提供）：人类肺癌的发生涉及遗传和表观遗传变化的积累，这些变化导致正常肺上皮、原位癌和最终的侵袭性和转移性癌症的改变。TGF-¿-诱导的肿瘤抑制功能的丧失被认为在这一转变中起着关键作用。肺癌对TGF- II型受体（T - RII）的耐药主要是通过TGF- II型受体（T - RII）表达的缺失而发生的，我们的初步数据表明，77%的人类肺癌中T - RII的表达缺失或弱。然而，目前尚不清楚在肺肿瘤发生过程中T¿RII表达是如何丢失的。我们最初的实验结果表明，MAPK/ERK通路的激活通过组蛋白去乙酰化导致T¿RII下调，而DNA超甲基化对T¿RII启动子活性没有影响。此外，我们观察到TGF-¿诱导的肿瘤抑制功能在TGF-¿抗性肺癌细胞中通过外源性T¿RII表达或通过组蛋白去乙酰化酶（HDAC）抑制剂（HDI）治疗得以恢复。由于大多数肺肿瘤由于T - RII的缺失而对TGF-¿产生耐药性，我们认为TGF-¿途径可能是hdi化疗干预的潜在靶点。我们提出以下假设：1)T¿RII在肺癌中的表达缺失主要是由于表观遗传改变，组蛋白去乙酰化，导致对TGF-¿诱导的抑瘤作用无应答。2)在恶性前期，TGF-¿的自分泌抗增殖作用占主导地位。然而，在肿瘤进展过程中，平衡发生了变化，TGF-¿的促生长作用在晚期变得明显。3) HDI恢复TGF-¿信号，MS-275是一种正在临床试验的抗癌药物，可能是肺癌治疗干预的潜在替代方案。这些假设将通过以下具体目的进行验证：1)确定肺癌中T¿RII下调的分子机制以及HDAC抑制剂如何靶向这一机制。2)确定TGF-¿过表达及TGF-¿信号通路在人肺癌细胞系中的生物学后果。本研究的长期目标是在分子水平上确定肺肿瘤对TGF-¿抑瘤功能产生耐药性的机制，并为hdi靶向TGF-¿通路在肺癌中的作用机制提供新的见解。增加对这些机制的了解将有助于改善肺癌的药物开发和治疗。

DESCRIPTION (provided by applicant): Lung carcinogenesis in humans involves an accumulation of genetic and epigenetic changes that lead to alterations in normal lung epithelium, in situ carcinoma, and finally invasive and metastatic cancers. The loss of TGF-¿-induced tumor suppressor function in tumors is believed to play a pivotal role in this transition. Resistance to TGF-¿ in lung cancers occurs mostly through loss of TGF-¿ type II receptor (T¿RII) expression, and our preliminary data suggest that expression of T¿RII is lost or weak in 77% of human lung cancers. However, it is not known how T¿RII expression is lost during lung tumorigenesis. Our initial experiments have resulted in an important observation that activation of the MAPK/ERK pathway causes down-regulation of T¿RII through histone deacetylation and that DNA hypermethylation has no effect on T¿RII promoter activity. In addition, we have observed that TGF-¿-induced tumor suppressor function is restored in TGF-¿ resistant lung cancer cells via exogenous T¿RII expression or with the treatment of histone deacetylase (HDAC) inhibitor (HDI). Since the majority of lung tumors are resistant to TGF-¿ due to loss of T¿RII, we believe that the TGF-¿ pathway could be a potential target of HDIs for chemotherapeutic intervention. We have formulated the following hypotheses: 1) Loss of T¿RII expression in lung cancer is mostly due to the epigenetic change, histone deacetylation, and promotes unresponsiveness to TGF-¿-induced tumor suppressor effects. 2) In the pre-malignant phase, the autocrine anti-proliferative effects of TGF-¿ predominate. However, the balance shifts during tumor progression, and growth-promoting effects of TGF-¿ become pronounced in the advanced stage. 3) Restoration of TGF-¿ signaling by the HDI, MS-275, an anticancer drug currently in clinical trials, may be a potential alternative for therapeutic intervention of lung cancers. These hypotheses will be tested by the following specific aims: 1) To determine the molecular mechanism of down-regulation of T¿RII in lung cancer and how that can be targeted by HDAC inhibitors. 2) To determine the biological consequences of over-expression of TGF-¿ and restoration of TGF-¿ signaling in human lung cancer cell lines. The long term objective of this study is to determine, at the molecular level, the mechanism by which lung tumors become resistant to TGF-¿ tumor suppressor function and to provide new insights into the mechanism by which HDIs target the TGF-¿ pathway in lung cancer. Increased understanding of these mechanisms should help to improve drug development and treatment of lung cancer.