Improving etoposide treatment of Ewing's sarcoma

改善依托泊苷对尤文氏肉瘤的治疗

• 批准号: 8703032
• 负责人: Alexander James Bishop
• 金额: $ 30.04万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703032
• 关键词: Alkylating Agents; Alkylation; Animal Model; Bioinformatics; Cancer Patient; Cell Survival; Cells; Childhood; Chromosomal translocation; Clinical; Critical Pathways; DNA Damage; Data; Diagnosis; Disease; Double-Stranded RNA; Drosophila genus; Effectiveness; Etoposide; Ewings sarcoma; Exposure to; FLI1 gene; Functional disorder; Genes; Genomics; Goals; Heterogeneity; Housing; Human; Individual; Investigation; Knowledge; Libraries; Life; Malignant Neoplasms; Mammalian Cell; Mediating; Methods; Methyl Methanesulfonate; Mus; Normal Cell; Oncogenic; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Positioning Attribute; Process; Publications; RNA Interference; Radiosurgery; Reagent; Research Infrastructure; Resistance; Role; Survival Rate; System; Technical Expertise; Teenagers; Testing; Time; Validation; Work; Xenograft Model; base; bone; cancer cell; cancer therapy; chemotherapy; cost; fitness; fusion gene; genome-wide; improved; inhibitor/antagonist; novel; novel strategies; outcome forecast; research study; response; soft tissue; standard care; young adult

DESCRIPTION (provided by applicant): Ewing's sarcoma is a childhood/young adult cancer. Unfortunately, many Ewing's sarcoma cancer patients are first diagnosed when the cancer cells are already spreading throughout the body, and these patients have a very poor prognosis. Therefore, identifying novel means to improve the effectiveness of the standard treatment of this cancer, a cocktail of drugs that includes etoposide, would be of immediate benefit. This proposal will provide the basis for novel strategies in the treatment of human cancer. Towards this goal, our work has been to identify the mechanisms that a normal (non-cancer) cell uses to survive exposure to an agent such as etoposide. The first part of our hypothesis is that we can identify novel human etoposide survival mechanisms from a Drosophila RNAi screen. We plan to use this knowledge to determine whether any etoposide survival mechanisms are altered in Ewing's sarcoma cancer cells. The second part of our hypothesis is that we can target etoposide survival mechanisms to restore or improve the effectiveness of etoposide therapy depending on what has been altered in the cancer cell. To achieve these goals, we will build from our currently established methods of identifying survival mechanisms in cells from a model organism; Drosophila cells. Once these genes are determined in Drosophila cells, we can test whether the same genes contribute to survival in mammalian cells. Indeed, we already successfully used this strategy to identify novel alkylation survival genes and pathways in mouse and human cells and demonstrated that pathways critical in Drosophila are also involved in mammalian damage response. The advantage of using fruit fly cells is that they share the same processes to survive exposure to an agent such as etoposide as human cells and we can efficiently, rapidly and cost-effectively ask whether removing any one gene alters the ability of a cell to survive etoposide treatment. This provides us with the ability to identify novel genes/mechanisms involved in cell survival. We will then demonstrate that the survival processes we identify in fruit fly cells are also used in mammalian cells. For this we plan to use human Ewing's sarcoma cells. In Aim 1, we propose to leverage our strategy, first completing the validations for a genomic survival screen to etoposide, identifying survival mechanisms, and then we will determine which of these mechanisms are altered in Ewing's sarcoma cells in a EWS/FLI1 dependent manner and which can be targeted to sensitize these cells to etoposide. In Aim 2, we will directly test the functionality of already identified survival mechanisms (and any identified from Aim 1) in a set of Ewing's sarcoma cancer cells, demonstrating any underlying heterogeneity in these cancers, and whether targeting these different pathways effects etoposide sensitivity in these cells. We are uniquely positioned to carry out the proposed work with the necessary infrastructure, collaborators and technical expertise, as demonstrated by our publications and our preliminary data that supports our hypothesis. Ultimately, our goal is to improve etoposide treatment of Ewing's sarcoma.

描述（由申请人提供）：尤因的肉瘤是童年/年轻的成人癌。不幸的是，当癌细胞已经在整个体内扩散时，许多Ewing的肉瘤癌患者首先被诊断出来，并且这些患者的预后较差。因此，确定提高该癌症标准治疗的有效性的新颖手段，包括依托泊苷在内的药物鸡尾酒将是直接的好处。该提案将为治疗人类癌症的新策略提供基础。为了实现这一目标，我们的工作是确定一种正常（非癌症）细胞使用的机制，可在依托泊苷（例如依托泊苷）中生存。我们假设的第一部分是我们可以从果蝇RNAi筛查中鉴定出新型的人类依托泊苷生存机制。我们计划利用这些知识来确定尤因的肉瘤癌细胞中是否改变了依托泊苷生存机制。我们假设的第二部分是，我们可以针对依托泊苷生存机制来恢复或提高依托泊苷治疗的有效性，具体取决于癌细胞中发生的变化。为了实现这些目标，我们将从目前确定的模型生物体中细胞中生存机制的方法来建立；果蝇细胞。一旦这些基因在果蝇细胞中确定，我们就可以测试相同的基因是否有助于哺乳动物细胞的存活。确实，我们已经成功地使用了该策略来鉴定小鼠和人类细胞中新型的烷基化存活基因和途径，并证明果蝇中至关重要的途径也参与了哺乳动物损伤的反应。使用果蝇细胞的优势在于，它们共享相同的过程，可以在依托泊苷等药物（例如人类细胞）中幸存下来，我们可以有效，快速和成本地询问去除任何基因是否会改变细胞生存依托泊苷治疗的能力。这为我们提供了鉴定与细胞存活有关的新型基因/机制的能力。然后，我们将证明我们在果蝇中鉴定的生存过程也用于哺乳动物细胞中。为此，我们计划使用人类尤因的肉瘤细胞。在AIM 1中，我们建议利用我们的策略，首先完成基因组生存筛查的验证以依托泊苷，识别生存机制，然后我们将确定以EWS/FLI1依赖性方式改变了Ewing的肉瘤细胞中哪些机制，并且可以针对这些细胞来敏感这些细胞来敏感这些细胞来敏感这些细胞。在AIM 2中，我们将直接测试一组Ewing的肉瘤癌细胞中已经鉴定出的生存机制（以及从AIM 1中鉴定出的任何鉴定出的生存机制）的功能，证明这些癌症中的任何潜在异质性，以及针对这些不同的途径是否影响这些细胞中的依托泊剂敏感性。正如我们的出版物和支持我们假设的初步数据所证明的那样，我们有独特的位置，可以使用必要的基础架构，合作者和技术专长进行拟议的工作。最终，我们的目标是改善对尤因肉瘤的依托泊苷治疗。