Treatment resistance of rectal cancers: identification and functional validation of novel therapeutic targets

直肠癌的治疗耐药性：新治疗靶点的鉴定和功能验证

• 批准号: 50704690
• 负责人: Privatdozent Dr. Marian Grade
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Kinderchirurgie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/50704690?language=en
• 关键词: Treatment; resistance; rectal; cancers; identification

We recently demonstrated that gene expression profiling might be useful for predicting the response of rectal carcinomas to preoperative chemoradiotherapy (CT/RT). Based on T-level downsizing, 54 genes showed significantly different expression levels between responders and nonresponders. While a major objective of subproject 1 is to prospectively validate this gene set in a much larger cohort of patients, the present subproject aims to functionally validate these genes by modifying their expression levels in cancer cell lines. We will therefore screen established CRC (colorectal cancer) cell lines to identify those cell lines with high expression levels for genes which were upregulated in resistant primary tumors. The functional validation will be pursued by RNA interference-mediated knockdown and assessment of the consequences of this knockdown relative to exposure to CT/RT. These experiments will be supported by establishing cell lines from responsive and resistant rectal adenocarcinomas. We anticipate that this process of functional validation will unveil relevant pathways for resistance to CT/RT. This would be a first step toward identifying small molecules that modify these pathways such that a priori resistant cell lines, and eventually primary tumors, could be sensitized to CT/RT in vitro.

我们最近证明，基因表达谱可能有助于预测直肠癌对术前放化疗（CT/RT）的反应。基于t水平缩减，54个基因在应答者和无应答者之间的表达水平有显著差异。虽然子项目1的主要目标是在更大的患者队列中前瞻性地验证该基因集，但目前的子项目旨在通过修改这些基因在癌细胞系中的表达水平来功能性地验证这些基因。因此，我们将筛选已建立的CRC（结直肠癌）细胞系，以确定那些在耐药原发肿瘤中上调的基因高表达的细胞系。功能验证将通过RNA干扰介导的敲低和评估这种敲低相对于暴露于CT/RT的后果来进行。这些实验将通过建立反应性和耐药性直肠腺癌细胞系来支持。我们预计这一功能验证过程将揭示CT/RT耐药的相关途径。这将是鉴定小分子修饰这些途径的第一步，从而使先天耐药细胞系和最终的原发性肿瘤能够在体外对CT/RT致敏。