Human in Mouse Modeling of HNSCC to Predict Resonse to Therapy

描述（由申请人提供）：本申请涉及广泛的挑战领域（06）使能技术和特定的挑战主题，06- ca -117：癌症发展，病理学和病理进展。头颈部鳞状细胞癌（HNSCC）是一种毁灭性的疾病，当诊断为晚期时，需要积极治疗。治疗包括至少两种，有时全部三种手术、放疗和化疗。由于上气道消化道结构在言语和吞咽中的关键作用，以及颈部脑神经和大血管的集中，标准的治疗方式经常导致不可接受的发病率，包括言语和吞咽缺陷、肩部功能障碍、颈动脉硬化加速、口干、牙关紧闭、淋巴水肿和颈部肌肉纤维化。靶向药物和个体化药物有望提高反应率，同时降低治疗相关的发病率；然而，测试靶向药物治疗HNSCC的标准临床试验不足以发现可能有效的药物，特别是如果疗效仅限于一小部分患者。临床试验的费用，符合条件的HNSCC患者数量有限，以及预期靶向药物的中低反应率表明，开发用于临床前测试的新工具来识别肿瘤内预测反应的分子特征将是有用的。我们正在开发技术，以可靠地创建低成本和易于处理的原发性HNSCC人鼠模型，该模型基于短期培养（1-5天），然后植入小鼠。该模型的一个优点是原发肿瘤是癌细胞的来源，由于目前这种非典型异种移植模型的成功率约为75%，因此可能代表了HNSCC的遗传多样性。另一个优点是，在建模之前，可以设计肿瘤来表达荧光素酶，这样就可以很容易地监测肿瘤的生长和反应，而无需牺牲动物。拟议研究的目的是继续开发这种体内癌症模型，该模型有望提高HNSCC药物开发的效率并降低成本。我们将对通过孢子间临床试验获得的组织进行建模，该试验旨在确定肿瘤对EGFR抑制剂、src抑制剂或EGFR和src抑制剂联合反应的分子特征。携带模拟肿瘤的小鼠将与产生模拟肿瘤的患者使用相同的药物进行治疗。未经治疗的患者肿瘤的分子特征将与衍生模型肿瘤进行比较，期望模型肿瘤将最接近于它们衍生的母肿瘤。该临床试验旨在检测与EGFR或src抑制相关的分子改变。将对模拟肿瘤进行研究，以确定它们是否对反映母体肿瘤反应的相同药物治疗有分子改变。验证模型肿瘤的分子和反应特征与母体肿瘤相似是该模型发展的下一个关键步骤。一旦验证，原发性HNSCC的人鼠模型将是最准确的HNSCC体内模型，可用于临床前环境，预测对单个或联合靶向治疗的反应。然后，人鼠模型中产生反应的肿瘤的特征可以用于临床试验，这样最有可能产生反应的肿瘤患者就会被招募进来。发展改良的人类癌症动物模型，可以准确地指导临床试验患者的选择，这将减少由于临床试验中低反应或无反应而导致的癌症治疗的严重失败率。我们预计该模型可以很容易地扩展到其他鳞癌，如肺癌、食道癌和子宫颈癌。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-CA-117: Cancer Development, Pathology, and Pathological Progression. Head and neck squamous cell carcinoma (HNSCC) is a devastating disease that is treated aggressively when diagnosed at late stages. Treatment includes at least two and at times all three modalities of surgery, radiation, and chemotherapy. Due to the critical role of structures of the upper aerodigestive tract in speech and swallowing and due to the concentration of cranial nerves and major blood vessels in the neck, standard therapeutic modalities frequently result in unacceptable morbidity including speech and swallowing defects, shoulder dysfunction, accelerated arteriosclerosis of the carotid, xerostomia, trismus, lymphedema and neck muscle fibrosis. Targeted agents and individualized medicine hold the promise of increasing response rates while decreasing treatment related morbidity; however, standard clinical trials to test targeted agents on HNSCC are inadequate for detecting agents that may be effective, especially if efficacy is limited to a small percentage of patients. The expense of clinical trials, the limited number of HNSCC patients eligible, and the expected moderate to low response rate for targeted agents suggest that development of new tools for pre-clinical testing to identify molecular characteristics within tumors that predict response would be useful. We are developing techniques to reliably create a low cost and tractable human-in-mouse model of primary HNSCC that is based on short-term culture (1-5 days) followed by implantation into mice. One advantage of this model is that primary tumors are the source of the cancer cells and since the current success rate with this atypical xenograft model is ~75%, the genetic diversity of HNSCC is likely to be represented. Another advantage is that before modeling, tumors can be engineered to express luciferase so that tumor growth and response can be easily monitored without animal sacrifice. The purpose of the proposed studies is to continue development of this in vivo cancer model that holds the promise to increase the efficiency and decrease the cost of drug development for HNSCC. We will model tissue obtained through an inter-SPORE clinical trial designed to determine molecular characteristics of tumors in response to EGFR inhibitors, src inhibitors, or the combination of EGFR and src inhibitors. Mice harboring modeled tumors will be treated with identical drugs as patients from which the modeled tumors were derived. Molecular characteristics of untreated patient tumors will be compared to derivative modeled tumors with the expectation that the modeled tumors will most closely resemble the parent tumor from which they were derived. The clinical trial is powered to detect molecular alterations associated with EGFR or src inhibition. Modeled tumors will be investigated to determine if they have molecular alterations in response to treatment with identical agents that reflect response of the parent tumors. Validation that molecular and response characteristics of the modeled tumors resemble those of the parent tumor is the next and critical step in development of this model. Once validated, the human-in-mouse model of primary HNSCC will be the most accurate in-vivo model of HNSCC and can be used in a pre-clinical setting to predict response to individual or combinations of targeted therapy. Characteristics of responding tumors from the human-in-mouse model could then be used to inform clinical trials so that patients with tumors most likely to respond would be enrolled. Development of Improved animal models of human cancer that can accurately guide clinical trial patient selection would decrease the abysmal failure rate for investigational cancer therapeutics due to low or no response in clinical trials. We anticipate that this model could be easily expanded to other squamous cancers such as lung, esophagus, and uterine cervix. PUBLIC HEALTH RELEVANCE: Existing pre-clinical models of human cancer are inadequate to predict response to targeted agents as evidenced by the low approval rates for drugs that enter clinical trials. We propose to develop a human-in-mouse model of head and neck squamous cell carcinoma that more accurately represents human head and neck cancer. We will validate the modeling and response accuracies of this in vivo model of human cancer using data gathered through an interSPORE Phase II clinical trial designed to determine molecular alterations associated with targeted therapy in head and neck squamous cell carcinoma.