Targeting SREBP-1 regulated fatty acid synthesis pathway to treat glioblastoma

描述（由申请人提供）：EGFR是PI3K信号的关键激活因子，在近50%的GBMs中被扩增和/或突变，与其他改变的信号级联合作，已被证明在胶质母细胞瘤（GBM）的发生和进展中发挥关键作用，这表明它是一个引人注目的分子靶点。然而，在临床上使用小分子抑制剂厄洛替尼和吉非替尼靶向EGFR的尝试失败了，导致相对较少的持续时间很短的临床反应。由于PI3K信号的反馈激活，在mTOR水平上靶向下游通路的尝试也失败了。因此，需要针对egfr激活的GBMs的新方法。最近的研究表明，EGFR的一些关键的致癌特性是通过它们对细胞代谢的影响来介导的。我们最近发现了一个以前没有预料到的结果，即EGFR信号通过改变细胞代谢来促进肿瘤存活。通过研究GBM患者样本，包括接受EGFR酪氨酸激酶抑制剂治疗的患者、细胞系和小鼠模型，我们证明了EGFR/PI3K/Akt信号通过脂肪生成的主要转录调节因子SREBP-1促进脂肪酸合成。更重要的是，我们已经证明EGFR激活的GBMs高度依赖SREBP-1介导的脂肪酸合成，因此阻止SREBP-1激活会促进携带突变EGFR的GBMs的大量凋亡。本文提出了一种治疗含有扩增或本构激活EGFR的GBMs的有效新策略。我们提供了令人信服的分子证据，证明基因抑制SREBP-1切割可杀死egfr激活的GBMs。为了将这些发现应用于临床，有必要确定脂肪酸合成途径的最佳靶点，并选择和测试可能用于临床的药理学抑制剂。在本提案中，我们将使用遗传和药理学方法来确定SREBP-1介导的脂肪酸合成途径中最有效的分子靶点和抑制剂。初步数据显示，SREBP-1抑制剂fatostatin可显著抑制前列腺癌细胞系和GBM细胞系的细胞增殖。令人兴奋的是，脂肪抑制素治疗以剂量依赖的方式显著导致GBM细胞死亡。重要的是，SREBP-1调节的脂肪酸合成途径中的关键酶ACL、ACC和FAS已被证明在肿瘤生长中发挥重要作用，抑制剂radicicol （ACL抑制剂）、TOFA （ACC抑制剂）和C75 （FAS抑制剂）已被证明对癌细胞生长具有抑制作用。我们的初步数据表明，TOFA和C75能有效抑制GBM细胞生长并诱导细胞死亡，特别是在EGFR激活的细胞中。因此，确定这些抑制剂对GBM治疗的抗癌效果，为靶向致命癌症开辟一条有希望的新途径是很有希望的。这项研究的完成可能为支持I期临床试验提供必要的临床前数据。

DESCRIPTION (provided by applicant): EGFR, a critical activator of PI3K signaling is amplified and/or mutated in nearly 50% of GBMs, in collaboration with other altered signaling cascades, has been shown to play a critical role in the development and progression of glioblastoma (GBM), suggesting that it is a compelling molecular target. However, attempts to target EGFR in the clinic with the small molecule inhibitors erlotinib and gefitinb have failed, resulting in relatively few clinical responses of very short duration. Attempts to target the pathway downstream at the level of mTOR have also failed due to feedback activation of PI3K signaling. Thus, new approaches towards targeting EGFR-activated GBMs are needed. Recent work suggests that some of the critical oncogenic properties of EGFR are mediated through their effect on cellular metabolism. We have recently uncovered a previously unsuspected result by which EGFR signaling promotes tumor survival by altering cellular metabolism. By studying GBM patient samples, including patients treated with EGFR tyrosine kinase inhibitors, cell lines and a mouse model, we have demonstrated that EGFR/PI3K/Akt signaling promotes fatty acid synthesis through the master transcriptional regulator of lipogenesis, SREBP-1. More importantly, we have shown that EGFR-activated GBMs are highly dependent upon SREBP-1-medaited fatty acid synthesis, so that preventing SREBP-1 activation promotes massive apoptosis of GBMs bearing mutated EGFR. This paper suggests a powerful new strategy for treating GBMs bearing amplified or constitutively activated EGFR. We provide compelling molecular evidence that genetic inhibition of SREBP-1 cleavage kills EGFR-activated GBMs. To move these findings into the clinic, it is essential to identify the optimal points in the fatty acid synthesis pathway to target, and that we select and test pharmacological inhibitors that can potentially be used in the clinic. In this proposal, we will use genetic and pharmacological approaches to identify the most effective molecular target and inhibitor within the SREBP-1 mediated fatty acid synthesis pathway. In preliminary data, SREBP-1 inhibitor fatostatin was shown to significantly inhibit cell proliferation of prostate cancer cell line and of GBM cell line. Excitingly, fatostatin treatment markedly leads to GBM cell death in dose-dependent manner. Importantly, the key enzymes ACL, ACC and FAS in SREBP-1 regulated fatty acid synthesis pathway have already been shown to play an important role in cancer growth, the inhibitors radicicol (ACL inhibitor), TOFA (ACC inhibitor) and C75 (FAS inhibitor) were shown potent in inhibition of cancer cell growth. Our preliminary data indicated TOFA and C75 were potent to inhibit GBM cell growth and induce cell death, particularly in EGFR activated cells. So it is promising to determine the anti-cancer effect of these inhibitors for GBM treatment, to open a promising new avenue to target the deadly cancer. Completion of this study is likely to provide necessary pre-clinical data to support a phase I clinical trial. PUBLIC HEALTH RELEVANCE: Glioblastoma (GBM) is one of the most deadly cancers, with patient survival averaging 12-18 months, despite surgery, radiation, and chemotherapy. We have recently uncovered a previously undescribed result by which EGFR signaling promotes tumor survival by activating SREBP-1 regulated fatty acid synthesis pathway. We identified SREBP-1 as a potential molecular target in GBM therapies; therefore, to move these findings into the clinic, it is essential to identify the optimal target points in the fatty acid synthesis pathway and to select and test pharmacological inhibitors that can potentially be used in the clinic. Completion of this study is likely to provide necessary pre-clinical data to support a phase I clinical trial in GBM and probably other cancers with activated EGFR signaling, and to promote developing potential drugs to treat cancer patients and to improve patient survival.