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

头颈癌在确诊后由于复发率高而构成巨大的治疗挑战。 局部晚期疾病的治疗。放射治疗联合顺铂已经成为治疗的标准。 在过去的15年里，对头颈部癌症进行非手术治疗，最近没有任何治疗方法 改善与人类乳头瘤病毒(HPV)无关的头颈部癌症预后的研究进展 感染。HPV阴性的头颈部癌的临床前模型对提高认识至关重要 对这些肿瘤的生物学进行研究，以设计新的治疗策略。目前最可用的临床前头部 颈部癌症模型利用免疫缺陷小鼠的异种移植或同基因移植肿瘤模型， 它们具有有限的肿瘤异质性，并且不能概括人类肿瘤与 完整的免疫系统。缺乏模拟人类头颈部癌症发展的临床前模型 转移是研究肿瘤生物学和发现有效的新的 这种疾病的治疗方法。为了解决这一差距，本提案在空间和时间上采用了新颖的 限制性致癌物诱导和基因工程的小鼠头颈部鳞状细胞模型 免疫活性小鼠肿瘤对放化疗耐药机制的探讨 与放射治疗相结合的新疗法。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和颈部转移疾病发展的新方法 宫颈癌患者。在准备启动一项成功的独立研究计划时，收到了一份 K08奖将促进这些新的初级临床前肿瘤模型的认证。此外，K08大奖 将提供获得新知识和技能的机会，以研究基因改变和表观遗传学 影响肿瘤反应和治疗抵抗的变化。此外，它还将促进受保护的时间 重点培训赠款撰写、实验室管理和职业发展。拟议的研究是 创新，因为它使用了第一个空间和时间受限的肿瘤的临床前模型 由人类头颈癌中常见的基因突变引起的，以及 接触烟草中存在的与临床相关的致癌物质。这些新颖的模型将被用于测试 针对ATR DNA损伤反应通路和程序性细胞死亡蛋白1(PD-1)的假说 1)免疫检查点配合放射治疗将改善头部和头部的局部和远程控制 颈癌。这项研究将建立一个临床前平台，以提高对头颈部的理解 癌症生物学和评估与放射治疗相结合的新治疗方法 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.