The project addresses the identification and validation of new aims for a combinatorial therapy of Mcl-1-dependent types of cancer

该项目致力于确定和验证 Mcl-1 依赖性癌症组合疗法的新目标

• 批准号: 198544794
• 负责人: Dr. Franziska Ertel
• 金额: --
• 依托单位: Department of Biochemistry
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/198544794?language=en
• 关键词: project; addresses; identification; validation; new

Basic research has made crucial discoveries in understanding what triggers cancer development. As a result specific defects in cancer cells are now the target of new therapeutic drugs. However, each type of cancer harbours unique genetic alterations, creating the challenge to match a targeted therapy to a specific cancer indication. Also, gene mutations result in resistance to prevailing therapies. Traditionally, a very time-consuming process addresses the hurdles of human clinical trials to determine which patients will benefit from a drug combination. Another approach to address this issue is the principle of synthetic lethality. This refers to the identity of two genes whose knockouts individually are benign, but together their elimination results in cell lethality. For cancer therapy, the combination of two or more drugs could be used to impede the pathways of two synthetically lethal genes leading to cancer cell death. An example is bortezomid treatment of multiple myeloma and mantle cell lymphoma, which is an approved agent that targets the proteasome. As the pro-survival protein Mcl-1 rapidly turns over via the proteasome, this results in Mcl-1 induction and resistance to bortezomib. Combining bortezomib with the agent obatoclax that targets Mcl-1, results in strong synergies, suggesting a rational clinical development strategy. The project will analyze the role for synthetic lethality opportunities in cancer therapy, targeting Mcl-1. This protein is the ideal candidate, as cancer cells have evolved pathways to preserve antiapoptotic Mcl-1. The project will employ an RNAi screen to identify signal transduction pathways that act in synergy with Mcl-1 to provide pro-survival signals and therefore represent new therapeutic opportunities for drug development. Finally, prioritized hit validation assays will be carried out with identified targets.

基础研究在理解是什么引发癌症发展方面取得了重要发现。因此，癌细胞中的特定缺陷现在成为新治疗药物的目标。然而，每种类型的癌症都有独特的遗传改变，这就给靶向治疗与特定癌症适应症的匹配带来了挑战。此外，基因突变导致对流行疗法的耐药性。传统上，一个非常耗时的过程解决了人类临床试验的障碍，以确定哪些患者将受益于药物组合。处理这一问题的另一个办法是合成致命性原则。这是指两个基因的同一性，它们的敲除单独是良性的，但它们的消除一起导致细胞死亡。对于癌症治疗，两种或更多种药物的组合可用于阻止两种合成致死基因导致癌细胞死亡的途径。一个例子是硼替佐米治疗多发性骨髓瘤和套细胞淋巴瘤，这是一种批准的药物，靶向蛋白酶体。由于促存活蛋白Mcl-1通过蛋白酶体快速翻转，这导致Mcl-1诱导和对硼替佐米的抗性。将硼替佐米与靶向Mcl-1的药物obatoclax组合，产生强烈的协同作用，这表明了合理的临床开发策略。该项目将分析针对Mcl-1的合成致死机会在癌症治疗中的作用。这种蛋白质是理想的候选者，因为癌细胞已经进化出保留抗凋亡Mcl-1的途径。该项目将采用RNAi筛选来识别与Mcl-1协同作用的信号转导途径，以提供促生存信号，因此代表了药物开发的新治疗机会。最后，将使用已识别的靶标进行优先命中验证试验。