Dissecting Co-Dependent Pathways in Oral Cancers

剖析口腔癌的相互依赖性途径

• 批准号: 8916951
• 负责人: John Chadwick Brenner
• 金额: $ 90.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916951
• 关键词: Address; Ally; Automobile Driving; Bees; Biological Assay; Biological Models; CDK4 gene; Cell Line; Cell Proliferation; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Comb animal structure; Combined Modality Therapy; Cyclins; DNA; Data; Diagnosis; Disease; Eating; Epidermal Growth Factor Receptor; FGFR1 gene; Fibroblast Growth Factor Receptors; Frequencies; Gene Combinations; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genomics; Goals; Growth; Knowledge; Lesion; Libraries; Malignant Epithelial Cell; Medicine; Metalcaptase; Modeling; Mole the mammal; Molecular; Molecular Target; Mouse Cell Line; Mutate; Neoplasm Metastasis; Oral; PIK3CA gene; PIK3CG gene; Pathway interactions; Patients; Protocols documentation; RNA; Relapse; Resistance; Squamous cell carcinoma; Survival Rate; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Wing; Work; Xenograft procedure; design; improved; in vivo; in vivo Model; inhibitor/antagonist; malignant mouth neoplasm; member; mouth squamous cell carcinoma; next generation sequencing; novel; precision medicine; preclinical study; public health relevance; response; screening; small molecule; small molecule libraries; targeted treatment; therapeutic target; tool; transcriptomics; treatment strategy; tumor

 DESCRIPTION (provided by applicant): Over 50% of patients with advanced Oral cavity Squamous Cell Carcinomas (OSCCs) seen at major tertiary centers die within five years of diagnosis following relapse from frontline therapy. We believe that improvements to overall survival will be made by improving our ongoing precision medicine trials, in which the right therapies are given at the right time, but this requires a comprehensive understanding of molecular subsets of the disease. Despite the knowledge that has been gained from publicly available OSCC sequencing data and because of the diversity of drivers and lost suppressors, too few cases have been sequenced to molecularly stratify the disease on an integrated genomic and transcriptomic level. Importantly, several targeted therapies have been advanced for common molecular alterations including EGFR, FGFR1/3, PIK3CA, NOTCH, etc.; however, these often perform poorly as monotherapies due to innate genetic or compensatory resistance creating a strong need for rational combination therapy. In fact, various members of the NOTCH pathway are mutated in ~50% of all OSCCs, and while we and others have recently advanced WNT pathway inhibitors to clinical trials for this molecular subset, NOTCH-deficient tumors frequently harbor additional lesions that can confound the therapeutic benefits of targeted monotherapy. We have collected a unique set of surgically treated responsive and relapsed OSCC tumors, which we propose to study for the frequency of co-altered lesions using integrative genetic and transcriptomic sequencing. Through preliminary pooled CRISPR and small molecule screening of genetically defined OSCC cell line models, we will validate a strategy that defines targets for combination therapy. Further, we show preliminary results using surgically excised, ex vivo OSCC tissue as a model system to evaluate novel combination therapies. Leveraging these tools and techniques, we will test our central hypothesis that innate or compensatory pathways, which drive resistance to targeted monotherapies, can be identified through our integrative approach and exploited to develop effective combination protocols that overcome resistance. We will address this hypothesis with the following Aims: 1) Identify co-dependent molecular targets for combination therapy through integrative next generation sequencing in surgically non-responsive OSCC, 2) Define the combinations of genes and pathways pivotal for cell proliferation in OSCC cell lines using lentiviral CRISPR and small molecule libraries, 3) Develop combination treatment strategies for genetically defined OSCC using in vivo models. Our primary goal is to develop novel combination strategies to improve the survival of patients with OSCC through identification of co-dependent therapeutic targets.

 描述（由适用提供）：超过50％的高级口腔方形细胞癌患者（OSCC）请参阅主要三级中心在前线治疗后诊断后的五年内死亡。我们认为，通过改善我们正在进行的精密医学试验的改善将改善整体生存，其中适当的时间进行了正确的疗法，但这需要对疾病的分子亚群进行全面的了解。尽管已经从公开可用的OSCC测序数据中获得的知识以及由于驱动因素和补充剂的多样性，但很少有病例被测序以在综合基因组和转录组水平上对疾病进行分子分层。重要的是，已经采用了几种靶向疗法，用于用于常见分子改变，包括EGFR，FGFR1/3，PIK3CA，Notch等。但是，由于先天的遗传或补偿性抗性，这些表现通常是单一疗法，因此对合理组合疗法产生了强烈的需求。实际上，在所有OSCC的约50％中，Notch途径的各种成员都被突变，尽管我们和其他人最近对该分子子集进行了临床试验，但缺陷型缺陷肿瘤经常带有其他病变，这些肿瘤经常带有可能使靶向单疗法的治疗益处混淆的其他病变。我们已经收集了一套独特的手术治疗的反应性和继电器OSCC肿瘤，我们建议使用整合的遗传和转录组测序研究，以研究共同经验教训的频率。通过对基因定义的OSCC细胞系模型的初步合并CRISPR和小分子筛选，我们将验证一种策略，该策略定义了联合治疗的靶标。此外，我们使用手术出色的，体内OSCC组织作为评估新型组合疗法的模型系统的初步结果。利用这些工具和技术，我们将测试我们的中心假设，即可以通过我们的综合方法来识别先天或补偿性途径，这些途径可以鉴定出对目标单层的阻力，并探索以开发克服抗药性的有效组合方案。我们将以以下目的解决这一假设：1）通过在手术非反应性OSCC中进行组合的下一代测序来确定联合治疗的共依赖性分子靶标，2）定义基因和途径的组合，用于使用慢性分子的Comcinition Compinitions oscc Compinities oscc Compinities oscc Compinition oscciatienties Compinition os Compinition os Compinition os Compinition Compinition os Compinition oscciatientials 3）型号。我们的主要目标是制定新型的组合策略，通过鉴定共同依赖性治疗靶标，以提高OSCC患者的生存。