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

针对 KRAS 驱动的致癌癌症的合成致死靶向治疗

• 批准号: 8317974
• 负责人: David A Barbie
• 金额: $ 17.82万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317974
• 关键词: Achievement; Apoptotic; BCL1 Oncogene; Biochemical; Bioinformatics; Biological; Biological Assay; Biological Models; Cancer Etiology; Cell Line; Cell Survival; Cells; Clinical; Clinical Trials; Computer Analysis; Data Set; Dependency; Environment; Equilibrium; Family member; Gene Targeting; Genes; Genetic; Genotype; Goals; Human; In Vitro; Institutes; KRAS2 gene; Laboratories; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mentors; Mentorship; Modeling; Molecular Target; Mus; Mutation; Nature; Normal Cell; Oncogenes; Oncogenic; PIK3CA gene; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pre-Clinical Model; RNA Interference; Refractory; Resources; Screening procedure; Signal Pathway; Signal Transduction; Structure-Activity Relationship; TBK1 gene; Testing; Therapeutic; Thoracic Oncology; Training; Translating; Translations; Validation; Work; assay development; base; cancer cell; cancer therapy; career; career development; drug development; effective therapy; efficacy testing; in vivo; inhibitor/antagonist; killings; loss of function; model development; mouse model; mutant; novel; oncogene addiction; pre-clinical; public health relevance; research clinical testing; research study; small hairpin RNA; small molecule; success; therapeutic target; transcription factor; translational study; tumor; tumor growth; tumor xenograft

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.

描述（由申请人提供）：尽管最近在分子靶向癌症治疗方面取得了重大进展，但成功仍然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。新的系统遗传学方法有可能识别携带致癌突变的细胞中的替代功能依赖性，这一概念被称为“合成致死性”。“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，已经有可能鉴定和验证与常见癌基因如PIK 3CA和KRAS的已知和新的遗传共依赖性（Vasudevan，Barbie等人，Cancer Cell 2009，PMID：19573809; Barbie等人，Nature 2009，PMID：19847166）。该项目的目标是将这些合成的致命靶标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。具体而言，KRAS下游生存所需的非经典I：B激酶TBK 1将成为进一步机制研究、小分子筛选工作和临床前验证的重点。TBK 1介导的NF-：B生存信号通路的阐明将促进用于药物开发的有效的生物化学和基于细胞的测定，并突出其他潜在的治疗靶点。特异性抑制TBK 1或其他NF-：B信号传导组分的化合物将在体外表征对细胞活力的KRAS选择性作用，然后在小鼠模型系统中测试功效。这些实验的总体目标是鉴定有效的TBK 1/NF-：B小分子抑制剂，其在临床前模型系统中得到验证，并且最终可以在针对KRAS驱动的肺癌的基因型导向的临床试验中进行评估。此外，目前正在进行系统的努力，以表征广泛的癌症相关遗传改变的合成致死靶点。TBK 1的有效临床翻译可以作为开发基于合成-致死的癌症靶向治疗的模型。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突变肺癌有效靶向治疗的长期职业目标保持一致。William Hahn博士的指导，Broad研究所的资源和协作性质，以及MGH胸部肿瘤科的专家临床培训共同提供了一个理想的环境，以支持职业发展和实现这些目标。 公共卫生关系：就像一辆油门被卡住的汽车一样，癌细胞被推动它们分裂的癌基因陷入了不稳定的平衡。与其直接瞄准加速器，不如通过追求使癌细胞保持在路上的适应性来将癌细胞推向边缘。用有效的药物靶向这些替代弱点可能会导致杀死癌细胞的新方法，同时保留正常细胞。