Radiogenomic Credentialing of Head and Neck Cancer Models

头颈癌模型的放射基因组学认证

• 批准号: 10310511
• 负责人: Mukund Seshadri
• 金额: $ 59.75万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10310511
• 关键词: Adrenergic beta-Antagonists; Allografting; Appearance; Autologous; Bioinformatics; Biological Models; Biology; Cancer Model; Caring; Cetuximab; Cisplatin; Clinical; Coculture Techniques; Collaborations; Comprehensive Cancer Center; Credentialing; Critical Pathways; Critiques; Data; Development; Disease; Dissection; Drug Screening; Evaluation; Exhibits; FDA approved; Functional Imaging; Future; Gene Expression Profile; Genomics; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Histone Deacetylase Inhibitor; Human; Human Papillomavirus; Immunocompetent; Immunological Models; In Vitro; Investigation; Malignant Neoplasms; Mediating; Mind; Modeling; Molecular; Molecular Profiling; Multimodal Imaging; Mus; Mutation; Neoplasms; Organoids; Pathogenesis; Patients; Pharmaceutical Preparations; Propranolol; Publishing; Quality of life; Radiation; Radiation therapy; Radiogenomics; Radiology Specialty; Research Personnel; Resistance; Respiratory physiology; Safety; Siblings; Speech; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Trials; Treatment Efficacy; Treatment Protocols; Validation; Valproic Acid; Work; Xenograft procedure; base; biobank; biomarker discovery; cancer imaging; chemoradiation; comparative; drug candidate; drug efficacy; drug repurposing; experience; high-throughput drug screening; human disease; image guided; imaging biomarker; imaging modality; immune checkpoint blockade; immunological status; immunoregulation; in vivo; in vivo Model; innovation; insight; mouse model; multimodality; novel; novel strategies; novel therapeutics; patient derived xenograft model; patient population; patient response; pre-clinical; precision medicine; radiation response; research clinical testing; resistance mechanism; response; screening; standard of care; targeted agent; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor immunology; tumor xenograft

Abstract Head and neck squamous cell carcinomas (HNSCC) are aggressive neoplasms that result in debilitating changes in speech, appearance, and quality of life in humans. Response rates in HNSCC patients have remained relatively unchanged over the years, especially in patients with human papillomavirus (HPV) negative HNSCC highlighting the critical need for novel strategies to meet the therapeutic needs of this patient population. As recognized by PAR-17-245, a critical step in discovering novel therapies for HNSCC patients is the development of tumor models that can reliably recapitulate human disease biology, heterogeneity and therapeutic response. The overall goal of this application is to validate and credential a panel of patient- derived and immunocompetent models of HNSCC. Systematic and in-depth comparison of histopathologic, genomic, and therapeutic response profiles will be performed across multiple preclinical platforms in vitro (organoids) and in vivo (allografts/xenografts). Paired in vitro and in vivo models across these platforms will be used to assess their response to standard of care chemoradiation and immune checkpoint blockade. The models will also be used to screen the activity of novel and FDA-approved agents (‘drug repurposing’) targeting critical pathways implicated in the pathogenesis of HNSCC. The application builds on an existing collaboration between several investigators at Roswell Park Comprehensive Cancer Center with extensive experience and expertise in mammalian models, head and neck cancer, cancer imaging, tumor immunology, genomics, bioinformatics and cancer therapeutics. The project will employ innovative multimodal functional imaging methods to better define and enhance the true translational utility of mammalian models. The proposal will establish a robust panel of credentialed mammalian models of HNSCC and enable development of an integrated preclinical pipeline to assess efficacy of novel therapeutics, identify resistance mechanisms and enable biomarker discovery in HNSCC.

摘要 头颈部鳞状细胞癌（HNSCC）是侵袭性肿瘤，其导致使人衰弱的肿瘤。 人类语言、外貌和生活质量的变化。HNSCC患者的缓解率 多年来保持相对不变，特别是在人乳头瘤病毒（HPV）患者中 阴性HNSCC突出了对新策略的迫切需要，以满足该患者的治疗需求 人口正如PAR-17-245所认识到的，发现HNSCC患者新疗法的关键步骤是 开发能够可靠地概括人类疾病生物学、异质性和 治疗反应。该应用程序的总体目标是验证和认证一组患者- HNSCC的衍生和免疫活性模型。系统和深入地比较组织病理学， 基因组和治疗反应谱将在体外多个临床前平台上进行 （类器官）和体内（同种异体移植物/异种移植物）。这些平台的配对体外和体内模型将 用于评估他们对标准化放疗和免疫检查点阻断的反应。的 模型还将用于筛选新的和FDA批准的药物（“药物恢复”）的活性 靶向参与HNSCC发病机制的关键途径。该应用程序建立在现有的 罗斯威尔公园综合癌症中心的几名研究人员与广泛的 在哺乳动物模型、头颈癌、癌症成像、肿瘤免疫学、 基因组学、生物信息学和癌症治疗学。该项目将采用创新的多式联运功能 成像方法，以更好地定义和提高哺乳动物模型的真正翻译效用。该提案 将建立一个可靠的HNSCC哺乳动物模型小组，并开发一种 整合的临床前管道，以评估新疗法的疗效，确定耐药机制， 能够在HNSCC中发现生物标志物。