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、病理学和病理学进展。头颈部鳞状细胞癌（HNSCC）是一种毁灭性的疾病，在晚期诊断时进行积极治疗。治疗包括至少两种，有时所有三种方式的手术，放疗和化疗。由于上呼吸消化道的结构在语言和吞咽中的关键作用，并且由于颅神经和主要血管集中在颈部，标准治疗方式经常导致不可接受的发病率，包括语言和吞咽缺陷、肩功能障碍、颈动脉的加速动脉硬化、口干症、牙关紧闭症、水肿和颈部肌肉纤维化。靶向药物和个体化药物有望提高缓解率，同时降低治疗相关的发病率;然而，测试靶向药物对HNSCC的标准临床试验不足以检测可能有效的药物，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患者数量有限以及靶向药物的预期中至低应答率表明，开发用于临床前测试的新工具以鉴定预测应答的肿瘤内的分子特征将是有用的。我们正在开发技术，以可靠地创建一个低成本和易处理的人在小鼠模型的主要HNSCC是基于短期培养（1-5天），然后植入小鼠。该模型的一个优点是原发性肿瘤是癌细胞的来源，并且由于该非典型异种移植模型的当前成功率为~ 75%，因此可能代表HNSCC的遗传多样性。另一个优点是，在建模之前，可以将肿瘤工程化以表达荧光素酶，使得可以在不牺牲动物的情况下容易地监测肿瘤生长和反应。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其成本。我们将通过一项旨在确定肿瘤对EGFR抑制剂、src抑制剂或EGFR和src抑制剂组合反应的分子特征的inter-SPORE临床试验获得组织建模。携带模型肿瘤的小鼠将用与衍生模型肿瘤的患者相同的药物治疗。将未治疗患者肿瘤的分子特征与衍生模型肿瘤进行比较，预期模型肿瘤将最接近其来源的母体肿瘤。该临床试验有能力检测与EGFR或src抑制相关的分子改变。将研究模型肿瘤，以确定它们是否对相同药物治疗产生分子改变，以反映母体肿瘤的反应。验证建模肿瘤的分子和反应特征与母体肿瘤的分子和反应特征相似，是开发该模型的下一步也是关键的一步。一旦得到验证，原发性HNSCC的人-鼠模型将是HNSCC的最准确的体内模型，并且可以在临床前环境中用于预测对靶向治疗的单独或组合的响应。然后，来自人在小鼠模型的响应肿瘤的特征可以用于通知临床试验，以便最有可能响应的肿瘤患者将被招募。开发可以准确指导临床试验患者选择的人类癌症的改进动物模型将降低由于临床试验中低应答或无应答而导致的研究性癌症治疗的极低失败率。我们预计，这种模型可以很容易地扩展到其他鳞状细胞癌，如肺，食管，和子宫颈。 公共卫生相关性：现有的人类癌症临床前模型不足以预测对靶向药物的反应，这一点可以通过进入临床试验的药物的低批准率来证明。我们建议开发一个人在小鼠模型的头部和颈部鳞状细胞癌，更准确地代表人类头颈癌。我们将使用通过interSPORE II期临床试验收集的数据来验证这种人类癌症体内模型的建模和响应准确性，该临床试验旨在确定与头颈部鳞状细胞癌靶向治疗相关的分子改变。

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.