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，在晚期确诊时会进行积极的治疗。治疗包括至少两种，有时包括所有三种方式的手术、放疗和化疗。由于上呼吸道结构在说话和吞咽中的关键作用，以及由于颅神经和主要血管集中在颈部，标准的治疗方案经常导致不可接受的发病率，包括言语和吞咽缺陷、肩功能障碍、加速的颈动脉硬化、口干、痉挛、淋巴水肿和颈部肌肉纤维化。靶向药物和个体化药物有望在提高应答率的同时降低与治疗相关的发病率；然而，测试HNSCC靶向药物的标准临床试验不足以检测可能有效的药物，特别是当疗效仅限于一小部分患者时。临床试验的费用，符合条件的HNSCC患者的有限数量，以及靶向药物预期的中低应答率表明，开发新的临床前测试工具来确定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，以可靠地创建一种低成本和易处理的人在小鼠体内的原发HNSCC模型，该模型基于短期培养(1-5天)，然后植入小鼠体内。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为~75%，因此HNSCC的遗传多样性很可能被代表出来。另一个优点是，在建模之前，肿瘤可以被设计成表达荧光素酶，这样就可以很容易地监测肿瘤的生长和反应，而不需要牺牲动物。拟议研究的目的是继续开发这种体内肿瘤模型，以期提高HNSCC的药物开发效率并降低成本。我们将模拟通过孢子间临床试验获得的组织，以确定肿瘤对egfr抑制剂、src抑制剂或egfr和src抑制剂组合的分子特征的反应。携带模型肿瘤的小鼠将接受与模型肿瘤患者相同的药物治疗。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，期望建模的肿瘤将最接近于它们衍生的亲本肿瘤。这项临床试验旨在检测与EGFR或src抑制相关的分子变化。将对模型肿瘤进行调查，以确定它们在使用反映亲本肿瘤反应的相同试剂治疗后是否有分子变化。验证模拟肿瘤的分子和反应特征与亲本肿瘤相似是发展该模型的下一步也是关键一步。一旦得到验证，原发HNSCC的人-鼠模型将是HNSCC最准确的体内模型，并可用于临床前环境中预测对个别或联合靶向治疗的反应。然后，可以使用人在小鼠模型中对肿瘤有反应的特征来为临床试验提供信息，以便招募最有可能有反应的肿瘤患者。开发能够准确指导临床试验患者选择的改进的人类癌症动物模型，将降低由于临床试验反应低或没有反应而导致的癌症研究治疗的极大失败率。我们预计，这个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。 公共卫生相关性：现有的人类癌症临床前模型不足以预测靶向药物的反应，进入临床试验的药物的批准率很低就是明证。我们建议开发一种头颈部鳞状细胞癌的人在鼠模型，以更准确地代表人的头颈部癌。我们将使用通过SPORE第二阶段临床试验收集的数据来验证这一人类癌症体内模型的建模和响应准确性，该试验旨在确定与头颈部鳞状细胞癌靶向治疗相关的分子变化。

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.