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

基本信息

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
项目类别：
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

项目摘要

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）：尽管分子靶向癌症治疗最近取得了重大进展，但成功仍然仅限于一小部分致癌基因成瘾性肿瘤。已知含有一些最常见癌基因（例如 KRAS）的癌症仍然难以有效治疗。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“合成致死率”。事实上，通过基于癌细胞的 RNA 干扰 (RNAi) 筛选数据集的计算分析，已经可以识别和验证与常见癌基因（例如 PIK3CA 和 KRAS）的已知和新的遗传相关性（Vasudevan、Barbie 等人，癌细胞 2009，PMID：19573809；芭比等人，自然 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，重点关注 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 TBK1 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。阐明 TBK1 介导的 NF-:B 生存信号通路将有助于药物开发的有效生化和细胞检测，并突出其他潜在的治疗靶点。特异性抑制 TBK1 或其他 NF-:B 信号传导成分的化合物将在体外表征 KRAS 对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，在临床前模型系统中进行验证，并最终在 KRAS 驱动的肺癌的基因型导向临床试验中进行评估。此外，目前正在进行系统性的努力来表征各种与癌症相关的遗传改变的合成致死靶点。 TBK1 的有效临床转化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和计算生物学方法来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非常吻合。 William Hahn 博士的指导、布罗德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，共同为支持职业发展和实现这些目标提供了理想的环境。公共健康相关性：与油门卡住的汽车类似，癌细胞因癌基因的分裂而陷入不稳定的平衡。与其直接瞄准加速器，不如通过追求使癌细胞继续前进的适应来将其推向边缘。用有效的药物针对这些替代弱点可能会带来杀死癌细胞的新方法，同时不伤害正常细胞。