Dissecting Co-Dependent Pathways in Oral Cancers

剖析口腔癌的相互依赖性途径

• 批准号: 9271962
• 负责人: John Chadwick Brenner
• 金额: $ 92.58万
• 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/9271962
• 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; 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; Operative Surgical Procedures; Oral; PIK3CA gene; PIK3CG gene; Pathway interactions; Patients; Precision medicine trial; Protocols documentation; RNA; Relapse; Resistance; Squamous cell carcinoma; Survival Rate; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Wing; Xenograft procedure; design; improved; in vivo; in vivo Model; inhibitor/antagonist; malignant mouth neoplasm; member; molecular subtypes; mouth squamous cell carcinoma; next generation sequencing; novel; preclinical study; public health relevance; response; screening; small molecule; small molecule libraries; targeted treatment; therapeutic target; tool; transcriptome; 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（由申请人提供）：在主要三级中心发现的晚期口腔鳞状细胞癌 (OSCC) 患者中，超过 50% 在一线治疗复发后的五年内死亡。我们相信，总体生存率将得到改善。改善我们正在进行的精准医学试验，在正确的时间给予正确的治疗，但这需要全面了解该疾病的分子亚群，尽管我们已经从公开的 OSCC 测序数据中获得了知识。由于驱动因素和丢失抑制因素的多样性，很少有病例能够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，针对常见的分子改变（包括 EGFR、FGFR1/3、PIK3CA）已经开发出了几种靶向疗法。 、NOTCH 等；然而，由于先天遗传或代偿性耐药，这些药物通常作为单一疗法表现不佳，因此强烈需要合理的联合治疗。事实上，NOTCH 途径的各个成员都发生了突变。约占所有 OSCC 的 50%，虽然我们和其他人最近已将 WNT 通路抑制剂推进到该分子亚型的临床试验中，但 NOTCH 缺陷的肿瘤存在额外的病变，这些病变可能会影响靶向单一疗法的治疗效果。手术治疗的反应性和复发性 OSCC 肿瘤，我们建议通过对基因定义的 OSCC 细胞系进行初步汇集 CRISPR 和小分子筛选，使用综合遗传和转录组测序来研究共同改变病变的频率。此外，我们将使用手术切除的离体 OSCC 组织作为模型系统来验证确定联合治疗目标的策略，以利用这些工具和技术来测试我们的中心假设。通过我们的综合方法可以识别导致对靶向单一疗法产生耐药性的先天或补偿途径，并利用它们来开发克服耐药性的有效组合方案。我们将通过以下目标来解决这一假设：1）确定相互依赖的分子靶点。通过综合下一代测序对手术无反应的 OSCC 进行联合治疗，2) 使用慢病毒 CRISPR 和小分子文库定义对 OSCC 细胞系中细胞增殖至关重要的基因和途径的组合，3) 使用基因定义的 OSCC 开发联合治疗策略我们的主要目标是开发新的组合策略，通过识别相互依赖的治疗靶点来提高 OSCC 患者的生存率。