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

基础研究在了解引发癌症发展的原因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的治疗药物的目标。然而，每种类型的癌症都有独特的基因改变，这给针对特定癌症适应症的靶向治疗带来了挑战。此外，基因突变会导致对主流疗法产生耐药性。传统上，一个非常耗时的过程来解决人体临床试验的障碍，以确定哪些患者将从药物组合中受益。解决这一问题的另一种方法是合成致命性原则。这是指两个基因的同一性，它们单独的敲除是良性的，但它们的共同消除导致细胞致命。对于癌症治疗，两种或两种以上的药物联合使用可以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，这是一种被批准的靶向蛋白酶体的药物。由于促生存蛋白Mcl-1通过蛋白酶体快速翻转，这导致Mcl-1诱导并对硼替佐米产生耐药性。硼替佐米与靶向Mcl-1的obatoclax联合使用，具有较强的协同效应，是一种合理的临床开发策略。该项目将分析针对Mcl-1的合成致死性机会在癌症治疗中的作用。这种蛋白是理想的候选者，因为癌细胞已经进化出了保存抗凋亡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，从而提供促生存信号，从而为药物开发提供新的治疗机会。最后，将对确定的目标进行优先命中验证分析。

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.