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

采用新型头颈癌原发小鼠模型来克服放化疗耐药性

基本信息

批准号：
10453730
负责人：
Yvonne MARIE Mowery
金额：
$ 16.08万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453730
关键词：
Address Affect Antigen Presentation Award Cancer Biology Cancer Model Cancer Prognosis Cancer Therapy Evaluation Program Carcinogens Characteristics Cisplatin Clinical Clinical Trials Combined Modality Therapy Competence Credentialing DNA Damage DNA Sequence Alteration Data Analyses Dental Development Diagnosis Disease Distant Dose Epigenetic Process Evaluation Evolution Exposure to FAT gene Gene Mutation Genetic study Genetically Engineered Mouse Genomics Goals Grant HPV oropharyngeal cancer Head and Neck Cancer Head and Neck Squamous Cell Carcinoma High-Throughput Nucleotide Sequencing Human Human Papillomavirus Human papilloma virus infection Immune system Immunocompetent Immunodeficient Mouse Immunologic Surveillance Incidence Institutes Isogenic transplantation Knowledge Laboratories Leadership Lesion Malignant Neoplasms Mentorship Mission Modeling Molecular Mus Mutate Mutation Neoplasm Metastasis Neoplasm Transplantation Oral health Outcome PIK3CA gene Pathway interactions Patient-Focused Outcomes Patients Phase Phase II Clinical Trials Phosphotransferases Physicians Platinum Pre-Clinical Model Preparation Proteins Radiation therapy Recurrence Recurrent disease Refractory Disease Research Resistance Risk Factors Safety Scientist Signal Pathway Structure T-Lymphocyte Techniques Testing Therapeutic Time Tobacco Tobacco use Tobacco-Associated Carcinogen Training Translating Tumor Biology Tumor-infiltrating immune cells Writing Xenograft procedure advanced disease anti-PD1 therapy base bench to bedside cancer cell cancer therapy career career development chemoradiation clinically relevant craniofacial design head and neck cancer patient human model image guided radiation therapy immune checkpoint immune checkpoint blockade improved improved outcome in vivo Model inhibitor innovation malignant mouth neoplasm mouse model new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics pembrolizumab pre-clinical preclinical study programmed cell death protein 1 programs radiation response response skills standard of care therapy resistant transplant model treatment optimization treatment strategy tumor tumor heterogeneity tumor initiation tumor microenvironment tumor progression

项目摘要

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.

头颈癌在确诊后复发率高，对治疗提出了重大挑战