Radiogenomic Credentialing of Head and Neck Cancer Models

摘要 头颈部鳞状细胞癌(HNSCC)是一种侵袭性肿瘤，会导致身体虚弱。 人类语言、外表和生活质量的变化。HNSCC患者的应答率 多年来相对保持不变，特别是在人类乳头瘤病毒(HPV)患者中 阴性的HNSCC突出了迫切需要新的策略来满足患者的治疗需求 人口。正如PAR-17-245所承认的，为HNSCC患者发现新疗法的关键一步是 肿瘤模型的发展可以可靠地概括人类疾病的生物学、异质性和 治疗反应。此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。系统深入的组织病理学比较， 基因组和治疗反应曲线将在体外跨多个临床前平台进行 (有机物)和体内(同种/异种移植物)。通过这些平台配对的体外和体内模型将是 用于评估他们对标准护理、放化疗和免疫检查点封锁的反应。这个 模型也将被用来筛选新的和FDA批准的药物的活性(药物再利用) 靶向与HNSCC发病机制有关的关键通路。该应用程序基于现有的 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模式功能 成像方法，以更好地定义和增强哺乳动物模型的真正翻译效用。这项建议 将建立一个强大的HNSCC哺乳动物模型小组，并使 集成的临床前流程，以评估新疗法的疗效，确定耐药机制和 在HNSCC中启用生物标记物发现。

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.