权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

靶向SREBP-1调节脂肪酸合成途径治疗胶质母细胞瘤

基本信息

批准号：
8309127
负责人：
Deliang Guo
金额：
$ 22.88万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309127
关键词：
Apoptosis Cancer Patient Cell Death Cell Line Cell Proliferation Cells Clinic Clinical Clinical Data Clinical Trials Collaborations Data Development Dose Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Fatty Acids Feedback Genetic Glioblastoma Growth Growth Inhibitors In Vitro Inhibition of Cancer Cell Growth Malignant Neoplasms Mediating Metabolism Molecular Molecular Target Mus Mutate Oncogenic PC3 cell line Paper Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Play Property Radiosurgery Role SRE-1 binding protein Sampling Signal Transduction Testing Work Xenograft Model cell growth chemotherapy human FRAP1 protein improved in vivo inhibitor/antagonist killings lipid biosynthesis monorden mouse model neoplastic cell novel strategies pre-clinical prevent response small molecule subcutaneous tumor tumor growth

项目摘要

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.

描述(申请人提供)：EGFR是PI3K信号的关键激活剂，在近50%的GBM中被扩增和/或突变，与其他改变的信号级联一起，已被证明在胶质母细胞瘤(GBM)的发生和发展中发挥关键作用，这表明它是一个引人注目的分子靶点。然而，小分子抑制剂erlotinib和gefitinb在临床上靶向EGFR的尝试都失败了，导致很短时间内的临床反应相对较少。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，需要以EGFR激活的GBM为靶点的新方法。最近的工作表明，EGFR的一些关键致癌特性是通过它们对细胞代谢的影响来调节的。我们最近发现了一个先前未被怀疑的结果，即EGFR信号通过改变细胞代谢来提高肿瘤存活率。通过研究GBM患者样本，包括使用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，我们已经证明了EGFR激活的GBM高度依赖于SREBP-1介导的脂肪酸合成，因此阻止SREBP-1的激活促进了携带突变的EGFR的GBM的大量凋亡。本文提出了一种强有力的新策略，用于治疗携带扩增的或成分激活的EGFR的GBM。我们提供了令人信服的分子证据，证明SREBP-1切割的遗传抑制会杀死EGFR激活的GBM。为了将这些发现应用于临床，至关重要的是确定脂肪酸合成途径中通向靶点的最佳点，并选择和测试可能在临床上使用的药物抑制剂。在这项提案中，我们将使用遗传学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物。初步数据显示，SREBP-1抑制剂Fate ostatin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，Fatostatin治疗显著地导致GBM细胞以剂量依赖的方式死亡。重要的是，在SREBP-1调节的脂肪酸合成途径中的关键酶ACL、ACC和Fas已经被证明在肿瘤生长中起着重要的作用，其中自由基(acl抑制剂)、TOFA(ACC抑制剂)和c75(Fas抑制剂)对癌细胞的生长具有明显的抑制作用。我们的初步数据表明，TOFA和C75能够有效地抑制GBM细胞的生长和诱导细胞死亡，尤其是在EGFR激活的细胞中。因此，确定这些抑制物在GBM治疗中的抗癌效果是很有希望的，为针对这种致命的癌症开辟了一条很有希望的新途径。这项研究的完成可能会提供必要的临床前数据，以支持I期临床试验。