Human in Mouse Modeling of HNSCC to Predict Resonse to Therapy

HNSCC 人鼠模型可预测治疗效果

• 批准号: 7814991
• 负责人: WENDELL G YARBROUGH
• 金额: $ 39.78万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7814991
• 关键词: Address; Aftercare; Animal Model; Animals; Area; Arteriosclerosis; Biological Markers; Biological Models; Biopsy; Blood Vessels; Cancer Model; Cancerous; Cervix Uteri; Characteristics; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Coupled; Cranial Nerves; Dasatinib; Data; Defect; Deglutition; Development; Diagnosis; Disease; Eligibility Determination; Engineering; Enrollment; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Epithelium; Erlotinib; Esophagus; Failure; Fibrosis; Functional disorder; Gene Amplification; Genetic Variation; Glioblastoma; Growth; Growth Factor Receptors; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; In Situ; Individual; Institution; Luciferases; Lung; Lymphedema; Malignant Neoplasms; Malignant neoplasm of lung; Medicine; Modality; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Mutation; Neck; New Agents; Other Genetics; Outcome; Parents; Pathology; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Placebos; Pre-Clinical Model; Primary Neoplasm; Radiation; Radiosurgery; Receptor Protein-Tyrosine Kinases; Reproduction spores; Resistance; Role; Sampling; Shoulder; Signal Transduction; Skeletal muscle structure of neck; Source; Speech; Staging; Structure; System; Techniques; Technology; Testing; Therapeutic; Time; Tissue Model; Trismus; Universities; Validation; Work; Xenograft Model; Xerostomia; base; cancer cell; cancer therapy; chemotherapy; combinatorial; cost; drug development; efficacy trial; established cell line; expectation; implantation; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; interest; kinase inhibitor; lung Carcinoma; model development; mouse model; novel; overexpression; pre-clinical; public health relevance; receptor; research clinical testing; response; src-Family Kinases; success; tool; tumor; tumor growth

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.

描述（由申请人提供）：此申请解决广泛的挑战领域（06）启用技术和特定挑战主题，06-CA-117：癌症发展，病理和病理进展。头颈部鳞状细胞癌（HNSCC）是一种毁灭性疾病，在晚期被诊断出时会受到积极治疗。治疗包括至少两种手术，放射和化学疗法的三种三种方式。 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纤维化。靶向药物和个性化药物有望提高反应率，同时降低治疗相关的发病率；但是，用于检测可能有效的药物的标准临床试验以测试针对HNSCC的靶向剂的试验不足，特别是如果功效仅限于一小部分患者时。临床试验的费用，有限的HNSCC患者资格的数量以及靶向药物的预期中度至低反应率表明，开发新的临床前测试工具以鉴定肿瘤中预测反应的分子特征，这将是有用的。我们正在开发技术以可靠地创建基于短期培养物（1-5天）的初级HNSCC的低成本和可疗程的人类模型，然后将其植入小鼠。该模型的一个优点是原发性肿瘤是癌细胞的来源，并且由于这种非典型异种移植模型的当前成功率为〜75％，因此HNSCC的遗传多样性很可能代表。另一个优点是，在建模之前，可以设计肿瘤以表达荧光素酶，以便无需动物牺牲即可轻松监测肿瘤的生长和反应。拟议的研究的目的是继续开发这种体内癌症模型，该模型有望提高效率并降低HNSCC药物开发成本。我们将通过一项旨在确定响应EGFR抑制剂，SRC抑制剂或EGFR和SRC抑制剂组合来确定肿瘤的分子特征的跨越临床试验进行建模。携带模型肿瘤的小鼠将用相同的药物治疗，该药物是从中得出建模肿瘤的患者。将未处理的患者肿瘤的分子特征与衍生化模型的肿瘤进行比较，预期模型的肿瘤将最类似于其衍生的父肿瘤。该临床试验有助于检测与EGFR或SRC抑制相关的分子改变。将研究模型的肿瘤，以确定它们是否对反映父肿瘤反应的相同药物的治疗响应分子改变。验证模型肿瘤的分子和反应特征类似于父肿瘤的肿瘤是该模型发展的下一个和关键步骤。一旦得到验证，主要HNSCC的人类模型将是最准确的HNSCC体内模型，可以在临床前环境中使用，以预测对靶向治疗的个体或组合的反应。然后，可以使用来自室内模型的肿瘤反应的特征来为临床试验提供信息，以便将招募最有可能反应的肿瘤患者。可以准确指导临床试验的人类癌症动物模型的发展发展将降低由于临床试验中低或没有反应而导致研究性癌症治疗的糟糕衰竭率。我们预计该模型很容易扩展到其他鳞状癌，例如肺，食道和子宫宫颈。 公共卫生相关性：现有的人类癌症前临床前模型不足以预测对靶向药物的反应，这是对进入临床试验的药物的低批准率证明的。我们建议开发一种人类的头颈部鳞状细胞癌模型，该模型更准确地代表了人头和颈部癌。我们将使用通过散布II期临床试验收集的数据来验证该体内人类癌症的建模和反应精度，旨在确定与头颈部鳞状细胞癌中靶向治疗相关的分子改变。