Regulating Sensitivity to Cancer Therapy with Engineered Transcription Factors

用工程转录因子调节癌症治疗的敏感性

• 批准号: 7590466
• 负责人: Charles A. Gersbach
• 金额: $ 1.67万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-16 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590466
• 关键词: Accounting; Address; Antibodies; Apoptosis; Apoptosis Inhibitor; Apoptotic; Apoptotic Pathway Deregulation; Autoimmune Diseases; Cancer Patient; Cancerous; Cell Death; Cell Surface Proteins; Cell surface; Cells; Cellular biology; Characteristics; Clinical Treatment; Clinical Trials; Complex; Development; Down-Regulation; Engineered Gene; Engineering; Equilibrium; Gene Expression; Gene Targeting; Gene Therapy Agent; Genes; Goals; Health; Homeostasis; Human; In Vitro; Laboratories; Libraries; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Organ; Outcome; Pathology; Phenotype; Process; Quality of life; Radiation therapy; Regulation; Repression; Research; Research Proposals; Resistance; Role; Screening procedure; Stimulus; Techniques; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor Suppression; Work; Zinc Fingers; anti-cancer therapeutic; base; cancer cell; cancer therapy; cell growth; cell transformation; cell type; chemotherapy; design; gene therapy; improved; in vivo; innovation; member; mortality; nervous system disorder; novel; receptor; receptor expression; response; subcutaneous; tool; transcription factor; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Deregulation of the apoptotic pathway is responsible for resistance to cancer therapeutics designed to induce cell death. Although there have been many advances in understanding apoptosis, the molecular characteristics involved in resistance or sensitivity to specific apoptotic stimuli are unclear. The identification of genes, which influence the cellular response to apoptosis-based therapeutics will significantly advance the field of cancer cell biology and the rational design of effective anti-cancer strategies. In particular, this research will focus on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which selectively stimulates cell death in cancer cells but not normal cells. However the mechanisms by which normal cells and particular transformed cells obtain resistance to TRAIL remain poorly understood. Our long-term goal is to identify novel gene targets for the design of effective anti-cancer therapeutics. The rationale for the proposed work is that libraries of engineered transcription factors are a unique and powerful tool for identifying genes involved in regulating sensitization or resistance to apoptosis-inducing cancer therapies. The overall objective of this proposal is to identify genes to be targeted for improved apoptosis-based therapeutics. Our hypothesis is that genes identified by libraries of engineered transcription factors (ETFs) will modulate sensitivity and resistance to TRAIL-mediated apoptosis. The objective will be accomplished by testing our hypothesis with the following specific aims: (1) Identify genes that regulate sensitivity to TRAIL-induced apoptosis; (2) Identify genes that regulate TRAIL-mediated suppression of tumor development; (3) Evaluate the role of TRAIL receptor and decoy receptor expression in regulating TRAIL sensitivity. Libraries of ETFs have been recently developed by the sponsor's laboratory to activate or repress the expression of genes associated with complex cellular phenotypes. We will use this tool to identify genes that confer resistance or enhance sensitivity to TRAIL in cancerous and normal cells using an apoptosis-based selection strategy. Additionally, we will use these libraries in combination with a human xenograft tumor model to identify genes that regulate TRAIL activity in vivo. Finally, ETFs will be used to regulate TRAIL receptor expression and elucidate the role of these receptors in selective TRAIL activity. The genes identified in this work will serve as the basis for designing cancer therapies that effectively eliminate cancer cells with minimal effects on normal tissues. These treatments will dramatically enhance the quality of life of cancer patients by maximizing the health of non-cancerous organs during treatment, limiting the need for repeated treatments, and decreasing mortality resulting from ineffective cancer therapy.

描述（由申请人提供）：凋亡途径的放松管制负责对旨在诱导细胞死亡的癌症治疗剂的抗性。尽管在理解凋亡方面取得了许多进步，但尚不清楚抗抗性或对特定凋亡刺激的敏感性所涉及的分子特征。影响基因对基于凋亡的治疗剂的细胞反应的鉴定将显着提高癌细胞生物学领域和有效抗癌策略的合理设计。特别是，这项研究将集中于肿瘤坏死因子相关的凋亡诱导配体（TRAIL），该配体（TRAIL）有选择地刺激癌细胞中但不是正常细胞中的细胞死亡。然而，正常细胞和特定转化细胞获得阻力的机制仍然鲜为人知。我们的长期目标是确定有效抗癌疗法设计的新型基因靶标。拟议工作的理由是，工程转录因子的库是识别用于调节敏感性或抗凋亡诱导癌症疗法的基因的独特而有力的工具。该提案的总体目的是确定要针对改善基于细胞凋亡的治疗剂的基因。我们的假设是，通过工程转录因子（ETF）鉴定的基因将调节对径向介导的细胞凋亡的敏感性和抗性。该目标将通过以下特定目的测试我们的假设来实现：（1）确定调节对踪迹诱导凋亡敏感性的基因； （2）确定调节径向介导的肿瘤发育抑制的基因； （3）评估跟踪受体和诱饵受体表达在调节跟踪敏感性中的作用。赞助商的实验室最近开发了ETF的文库，以激活或抑制与复杂细胞表型相关的基因的表达。我们将使用此工具来识别使用基于凋亡的选择策略赋予抗癌和正常细胞中抗癌症敏感性的基因。此外，我们将将这些文库与人类异种移植肿瘤模型结合使用来鉴定调节体内跟踪活性的基因。最后，ETF将用于调节跟踪受体的表达，并阐明这些受体在选择性跟踪活性中的作用。这项工作中鉴定出的基因将成为设计有效消除对正常组织影响最小的癌细胞的癌症疗法的基础。这些治疗方法将通过在治疗过程中最大化非癌性器官的健康，限制重复治疗的需求，并降低因癌症治疗无效而导致的死亡率，从而大大提高癌症患者的生活质量。