Employing Novel Primary Mouse Models of Head and Neck Cancer to Overcome Chemoradiation Resistance

头颈部癌症由于确诊后的高复发率而构成了重大的治疗挑战。 治疗局部晚期疾病。放射治疗同时顺铂已成为标准的护理 在过去的15年里，头颈部癌症的非手术治疗，最近没有治疗 改善与人乳头瘤病毒（HPV）无关的头颈癌预后的进展 感染HPV阴性头颈癌的临床前模型对于提高对HPV阴性头颈癌的认识至关重要。 研究这些肿瘤的生物学，以设计新的治疗策略。最新可用的临床前股骨头 和颈部癌症模型利用免疫缺陷小鼠中的异种移植物或同基因移植肿瘤模型， 其具有有限的肿瘤异质性，并且不再现人类肿瘤与肿瘤细胞的逐渐共同进化。 完整的免疫系统缺乏模拟人类头颈癌发展的临床前模型 转移是研究肿瘤生物学和发现有效的新的治疗方法的实质性障碍。 治疗这种疾病。为了解决这一差距，目前的建议采用新的空间和时间 限制性致癌物诱导和基因工程小鼠头颈部鳞状细胞模型 免疫活性小鼠中的癌症，以探究化学放射抵抗的机制并评估 与放射疗法的新的治疗组合。这项研究的长期目标是识别和测试 改善放射反应和减少头部转移性疾病发展的新方法， 颈部癌症患者。在准备启动一个成功的独立研究计划，收到一个 K 08奖将促进这些新的原发性临床前肿瘤模型的认证。此外，K 08奖 将提供获得新知识和技能的机会，以研究遗传改变和表观遗传 影响肿瘤反应和对治疗的抗性的变化。此外，它还将促进保护时间， 重点培训拨款写作，实验室管理和职业发展。拟议的研究是 创新，因为它采用了第一个空间和时间限制肿瘤的临床前模型 由人类头颈癌中常见的基因突变引起，沿着 暴露于烟草中存在的临床相关致癌物质。这些新模型将用于测试 假设靶向ATR DNA损伤反应途径和程序性细胞死亡蛋白1（PD-1）， 1)免疫检查点与伴随放射治疗将改善头部局部和远端控制， 颈癌这项研究将建立一个临床前平台，以提高对头颈部疾病的认识。 癌症生物学和评估新的治疗组合与放射治疗， 疾病

Head and neck cancer poses significant treatment challenges due to high rates of recurrence after definitive therapy for locally advanced disease. Radiation therapy with concurrent cisplatin has been the standard of care for non-surgical management of head and neck cancer for the past 15 years, with no recent therapeutic advances to improve outcomes for head and neck cancer that is unrelated to human papillomavirus (HPV) infection. Preclinical models of HPV-negative head and neck cancer are critical to improve the understanding of the biology of these tumors to devise novel treatment strategies. Most currently available preclinical head and neck cancer models utilize xenografts in immunodeficient mice or syngeneic transplant tumor models, which have limited tumor heterogeneity and do not recapitulate gradual co-evolution of human tumors with an intact immune system. This lack of preclinical models that mimic human head and neck cancer development and metastasis represents a substantial barrier to studying tumor biology and discovering effective new therapies for this disease. To address this gap, the current proposal employs novel spatially and temporally restricted carcinogen-induced and genetically engineered mouse models of head and neck squamous cell carcinoma in immunocompetent mice to interrogate mechanisms of chemoradiation resistance and to assess novel therapeutic combinations with radiation therapy. The long-term goal of this research is to identify and test new approaches to improve radiation response and to reduce development of metastatic disease for head and neck cancer patients. In preparation for launching a successful independent research program, receipt of a K08 Award will facilitate credentialing these novel primary preclinical tumor models. Moreover, a K08 Award will provide the opportunity to acquire new knowledge and skill sets to study genetic alterations and epigenetic changes affecting tumor response and resistance to therapy. In addition, it will facilitate protected time for focused training in grant writing, laboratory management, and career development. The proposed research is innovative because it employs the first preclinical models with spatially and temporally restricted tumors induced by genetic mutations that are commonly identified in human head and neck cancer, along with exposure to a clinically relevant carcinogen present in tobacco. These novel models will be used to test the hypothesis that targeting the ATR DNA damage response pathway and programmed cell death protein 1 (PD- 1) immune checkpoint with concomitant radiation therapy will improve local and distant control of head and neck cancer. This research will establish a preclinical platform for improving understanding of head and neck cancer biology and for evaluating new therapeutic combinations with radiation therapy for this difficult to treat disease.