Intervention of Ras-ERK-activated cancers

Ras-ERK 激活癌症的干预

• 批准号: 8754604
• 负责人: Hwa-Chain Robert Wang
• 金额: $ 15.43万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754604
• 关键词: Accounting; Address; Advanced Malignant Neoplasm; Adverse effects; Animals; Apoptosis; Apoptotic; Biochemical; Cell Death; Cell Death Induction; Cell Survival; Cells; Cisplatin; Clinical Trials; DNA; DNA Crosslinking Agent; Data; Development; Drug Metabolic Detoxication; Drug resistance; Effectiveness; Glutathione; Histone Deacetylase Inhibitor; Human; In Vitro; Induction of Apoptosis; Intervention; Knowledge; Left; Life; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Mitochondria; Molecular; Mutation; Normal Cell; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Predisposition; Quality of life; Reactive Oxygen Species; Recurrence; Regimen; Reporting; Resistance; Role; Signal Pathway; Therapeutic; Toxic effect; Transitional Cell Carcinoma; Translating; Treatment Efficacy; United States; United States Food and Drug Administration; Work; cancer cell; cell type; chemotherapy; effective intervention; effective therapy; improved; in vivo; innovation; public health relevance; success; tumor xenograft

DESCRIPTION (provided by applicant): The objective of this project is to develop a new strategy to increase therapeutic efficacy in controlling recurrence and progression of cancer cells carrying the activated Ras-ERK pathway (Ras-ERK-activated cancer cells), including transitional cell carcinomas (TCCs). TCCs account for more than 90% of urinary bladder cancers (UBC), and UBC is the fifth-most common cancer in the United States. Due to an increased tendency to recur and develop to invasive cancer, TCC requires life-long surveillance, making it the most expensive cancer to manage. Although current therapies are effective in short-term treatment of TCC, long- term management is still not optimal. Growing evidence reveals that genetic alterations result in aberrantly- regulated signaling pathways, such as Ras-ERK, and upregulated mitochondrial reactive oxygen species (ROS) machinery, leading to ROS elevation in TCC cells. Drugs such as the DNA-crossing agent cisplatin are capable of inducing ROS; however, drug resistance is reportedly associated with glutathione (GSH)- dependent detoxification in chemotherapy. Our preliminary studies suggest that the histone deacetylase inhibitor FK228 has the ability to effectively induce ROS and deplete GSH by itself in Ras-ERK-activated cancer cells, including TCC cells, and to synergistically induce cell death and reduce clonogenic survival when combined with cisplatin. Thus, the rationale of this project is that it wil advance our knowledge of i) targetable, aberrantly-upregulated, ROS-generating signaling pathways induced in the course of Ras-ERK- activated cancer development and ii) combined use of Food and Drug Administration (FDA)-approved, ROS-inducing and GSH-depleting agents to effectively intervene in Ras-ERK-activated cancers. Our central hypothesis is that augmentation of ROS to a lethal level in Ras-ERK-activated cancer cells (while leaving ROS at non-lethal levels in normal counterpart cells) and reduction of GSH-dependent drug resistance will induce selective cell death to achieve highly-effective intervention of cancer with minimal side effects. To address this hypothesis, we will pursue the effectiveness of ROS-inducing and GSH-depleting agents in control of Ras-ERK-activated TCC cells in vitro and in vivo. We will also identify ROS-mediated, pro- apoptotic mechanisms of aberrantly-regulated oncogenic pathways involved in increased cell death and reduced resistance to new drug regimens. Our project is innovative with a high impact in that molecular, biochemical, cellular, and animal studies of the new combined regimens of FDA-approved agents could be efficiently translated into clinical trials to improve chemotherapy toward controlling the development and recurrence of Ras-ERK-activated TCCs and ultimately improving quality of life for patients.

描述（由申请人提供）：该项目的目标是开发一种新策略，以提高控制携带激活 Ras-ERK 通路的癌细胞（Ras-ERK 激活癌细胞）的复发和进展的治疗效果，包括移行细胞癌（TCC）。 TCC 占膀胱癌 (UBC) 的 90% 以上，UBC 是美国第五大常见癌症。由于复发和发展为浸润性癌症的可能性增加，TCC 需要终身监测，使其成为治疗费用最高的癌症。尽管目前的疗法在 TCC 的短期治疗中是有效的，但长期管理仍然不是最佳的。越来越多的证据表明，基因改变会导致信号通路异常调节，例如 Ras-ERK，并上调线粒体活性氧 (ROS) 机制，从而导致 TCC 细胞中 ROS 升高。 DNA交叉剂顺铂等药物能够诱导ROS；然而，据报道耐药性与化疗中谷胱甘肽 (GSH) 依赖性解毒有关。我们的初步研究表明，组蛋白脱乙酰酶抑制剂 FK228 能够在 Ras-ERK 激活的癌细胞（包括 TCC 细胞）中有效诱导 ROS 并自行消耗 GSH，并与顺铂联合使用时协同诱导细胞死亡并减少克隆存活。因此，该项目的基本原理是，它将增进我们对以下方面的认识：i) 在 Ras-ERK 激活的癌症发展过程中诱导的可靶向、异常上调、ROS 生成信号通路，以及 ii) 食品和药物管理局的联合使用(FDA) 批准的 ROS 诱导剂和 GSH 消耗剂，可有效干预 Ras-ERK 激活的癌症。我们的中心假设是，Ras-ERK 激活的癌细胞中 ROS 增加至致死水平（而正常对应细胞中 ROS 保持在非致死水平）和 GSH 依赖性耐药性的减少将诱导选择性细胞死亡，以实现高度-有效干预癌症，副作用最小。为了解决这一假设，我们将在体外和体内研究 ROS 诱导剂和 GSH 消耗剂在控制 Ras-ERK 激活的 TCC 细胞中的有效性。我们还将确定 ROS 介导的、异常调节的致癌途径的促凋亡机制，这些机制涉及细胞死亡增加和对新药疗法的耐药性降低。我们的项目具有创新性，在分子、生化、细胞和动物研究方面具有重大影响，FDA 批准的新药物联合方案可以有效转化为临床试验，以改善化疗，控制 Ras-ERK 的发展和复发。激活 TCC，最终改善患者的生活质量。