Targeting TGF-beta Signaling in Lung Cancer

描述（由申请人提供）：人类肺癌发生涉及遗传和表观遗传变化的积累，导致正常肺上皮细胞改变、原位癌，最终导致浸润性和转移性癌症。TGF-β诱导的肿瘤抑制功能在肿瘤中的丧失被认为在这种转变中起着关键作用。对TGF-β的抵抗在肺癌中，主要通过TGF-β II型受体（T <$RII）表达的缺失发生，我们的初步数据表明，在77%的人肺癌中，T <$RII的表达缺失或减弱。然而，目前尚不清楚T <$RII表达是如何在肺肿瘤发生过程中丢失的。我们最初的实验已经导致了一个重要的观察结果，即MAPK/ERK通路的激活通过组蛋白去乙酰化引起T <$RII的下调，并且DNA超甲基化对T <$RII启动子活性没有影响。此外，我们还观察到TGF-β诱导的肿瘤抑制功能在TGF-β抗性肺癌细胞中通过外源性T <$RII表达或组蛋白脱乙酰酶（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-<$通路可能是HDI用于化疗干预的潜在靶点。我们提出了以下假设：1）肺癌中T <$RII表达的缺失主要是由于表观遗传变化，组蛋白去乙酰化，并促进对TGF-β诱导的肿瘤抑制作用的无反应性。2)在癌前阶段，TGF-β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-β的促生长作用在晚期变得明显。3)TGF-β的恢复MS-275是一种目前处于临床试验中的抗癌药物，可能是肺癌治疗干预的潜在替代品。这些假设将通过以下具体目标进行检验：1）确定肺癌中T <$RII下调的分子机制以及HDAC抑制剂如何靶向该机制。2)确定人肺癌细胞系中TGF-β过表达和TGF-β信号恢复的生物学后果。本研究的长期目标是在分子水平上确定肺肿瘤对TGF-β肿瘤抑制功能产生抗性的机制，并为HDI靶向肺癌中TGF-β通路的机制提供新的见解。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.