Synthetic-Lethal-Based Targeted Therapy for Oncogenic KRAS-Driven Cancer

描述（由申请人提供）：尽管最近分子靶向癌症治疗取得了重大进展，但成功仍然局限于一小部分癌基因成瘾肿瘤。已知含有一些最普遍的致癌基因的癌症，如KRAS，仍然难以有效治疗。新的系统遗传方法有可能识别携带致癌突变的细胞中的其他功能依赖性，这一概念被称为“合成致命性”。事实上，通过对基于癌细胞的RNA干扰（RNAi）筛选数据集的计算分析，已经有可能识别和验证已知的和新的与常见癌基因如PIK3CA和KRAS的遗传共依赖关系（Vasudevan， Barbie等，cancer Cell 2009, PMID: 19573809； Barbie等，Nature 2009, PMID: 19847166）。该项目的目标是将这些合成致死靶点转化为有效的基因型特异性癌症治疗，重点是kras驱动的肺癌，因为它仍然是一个棘手的临床问题。具体来说，KRAS下游生存所需的非规范I:B激酶TBK1将成为进一步机制研究、小分子筛选和临床前验证的重点。tbk1介导的NF-:B生存信号通路的阐明将促进有效的生物化学和基于细胞的药物开发分析，并突出其他潜在的治疗靶点。特异性抑制TBK1或其他NF-:B信号成分的化合物将被表征为kras对体外细胞活力的选择性影响，然后在小鼠模型系统中测试其功效。这些实验的总体目标是确定有效的TBK1/NF-:B小分子抑制剂，这些抑制剂在临床前模型系统中得到验证，并最终可以在kras驱动的肺癌的基因型导向临床试验中进行评估。此外，目前正在进行系统的努力，以表征一系列与癌症相关的遗传改变的合成致命靶标。TBK1的有效临床翻译可以作为开发基于合成致死性靶向治疗癌症的模型。该项目与应用功能遗传学和计算生物学方法确定癌症治疗新靶点的近期职业目标以及将这些发现转化为KRAS突变肺癌的有效靶向治疗的长期职业目标相一致。William Hahn博士的指导，Broad研究所的资源和合作性质，以及MGH胸部肿瘤科的专家临床培训，共同为支持职业发展和实现这些目标提供了理想的环境。

DESCRIPTION (provided by applicant): Despite recent significant advances in molecular targeted cancer therapy, success has remained limited to a small subset of oncogene-addicted tumors. Cancers known to harbor some of the most prevalent oncogenes, such as KRAS, remain refractory to effective treatment. Novel systematic genetic approaches have the potential to identify alternative functional dependencies in cells carrying cancer-causing mutations, a concept known as "synthetic lethality." Indeed, through computational analysis of cancer cell-based RNA interference (RNAi) screening datasets, it has been possible to identify and validate both known and novel genetic co- dependencies with common oncogenes such as PIK3CA and KRAS (Vasudevan, Barbie et al., Cancer Cell 2009, PMID: 19573809; Barbie et al., Nature 2009, PMID: 19847166). The goal of this project is to translate these synthetic lethal targets into effective genotype-specific cancer therapy, with a focus on KRAS-driven lung cancer, since it remains an intractable clinical problem. Specifically, the non-canonical I:B kinase TBK1, which is required for survival downstream of KRAS, will be the focus of further mechanistic studies, small molecule screening efforts, and pre-clinical validation. Elucidation of the TBK1-mediated NF-:B survival-signaling pathway will facilitate effective biochemical and cell-based assays for drug development and highlight other potential targets for therapy. Compounds that specifically inhibit TBK1 or other NF-:B signaling components will be characterized for KRAS-selective effects on cell viability in vitro, and then tested for efficacy in mouse model systems. The overall goal of these experiments is to identify effective TBK1/NF-:B small molecule inhibitors that validate in pre-clinical model systems and that can ultimately be evaluated in genotype-directed clinical trials for KRAS-driven lung cancer. Moreover, systematic efforts are currently underway to characterize synthetic lethal targets for a wide array of cancer-related genetic alterations. Effective clinical translation of TBK1 could serve as a model for development of synthetic-lethal-based targeted therapy in cancer in general. This project aligns well with the immediate career goal of applying functional genetic and computational biological approaches to identify novel targets for cancer therapy, and the long-term career goal of translating these findings into effective targeted therapy for KRAS mutant lung cancer. The mentorship of Dr. William Hahn, the resources and collaborative nature of the Broad Institute, and the expert clinical training in the MGH Thoracic Oncology division collectively provide an ideal environment to support career development and the achievement of these goals. PUBLIC HEALTH RELEVANCE: Similar to a car with a jammed accelerator, cancer cells are caught in a precarious balance by the oncogenes that push them to divide. Rather than targeting the accelerator directly, it may be possible to tip cancer cells over the edge by instead going after the adaptations that keep them on the road. Targeting these alternative vulnerabilities with effective drugs may lead to new ways to kill cancer cells, while sparing normal cells.