Colorado Head and Neck Cancer SPORE

科罗拉多头颈癌孢子

基本信息

批准号：
10704550
负责人：
Antonio Jimeno
金额：
$ 181.74万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704550
关键词：
Address Anatomy Basic Science Biological Models Biopsy Breathing Cancer Model Caring Cell Survival Cell physiology Cells Clinic Clinical Sciences Clinical Trials Colorado Combination immunotherapy Communication Cyclin D1 Data Data Science Dedications Development Disabled Persons Discipline Endothelium Epithelial-Stromal Communication Eragrostis Faculty Fostering Genetically Engineered Mouse Goals Grant Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Human Human Papillomavirus Immune Immune Evasion Immunocompetent Immunosuppression Immunotherapy Infiltration Investigational Therapies Lead Malignant neoplasm of salivary gland Malignant neoplasm of thyroid Modeling Molecular Morbidity - disease rate Mus Oncogenic Organ Pathogenesis Pathology Patients Pharmaceutical Preparations Phase Postdoctoral Fellow Prognostic Marker Proteins Quality of life Radiation therapy Recurrence Regimen Regulatory T-Lymphocyte Reproduction spores Research Research Personnel Research Project Grants Resistance Sampling Signal Transduction T-Lymphocyte Testing Therapeutic Therapeutic Intervention Therapeutically Targetable Tissues Tobacco Transforming Growth Factor beta Translating Translational Research Translations Treatment Efficacy Tumor-associated macrophages Underrepresented Minority Underrepresented Populations United States National Institutes of Health Vascular Endothelial Cell anticancer research base cancer cell cancer survival cancer therapy cancer type career chemoradiation clinical application design head and neck cancer patient humanized mouse improved improved outcome in situ vaccination in vitro Model in vivo inhibitor innovation monocyte mortality novel novel therapeutic intervention optimal treatments palliation participant enrollment patient derived xenograft model pharmacologic phase I trial pre-clinical predictive marker prognostic prognostic significance programmed cell death ligand 1 programs recruit research and development research clinical testing synergism targeted treatment therapeutic target therapy development translational cancer research tumor tumor microenvironment

项目摘要

PROJECT SUMMARY, Overall The main goal of the Colorado (CO) Head and Neck Cancer (HNC) SPORE is to advance translational research to improve survival and quality of life for HNC patients. Optimal treatment for HNC patients is critically important because the head and neck organs support critical functions such as breathing, nourishing and communicating, and thus HNC can lead to significant morbidity and mortality. The CO HNC SPORE takes advantage of our expertise in basic and clinical sciences, and uses unique model systems to identify novel molecular and cellular mechanisms of HNC pathogenesis targetable by therapeutic interventions to treat all cancer types arising from head and neck anatomic sites. Three projects cover the treatment spectrum of head and neck squamous cell carcinoma (HNSCC) and include both tobacco-related and human papillomavirus (HPV)-related HNSCC. Project 1 studies novel immunotherapy mechanisms by inhibiting EphB4-EFNB2 interactions between immune cells and the endothelium. It will test if blockade of EphB4-EFNB2 signaling at the tumor endothelial barrier hinders Tregs' and TAMs' ability to infiltrate and promote cancer survival or suppress Teff function. The applicability of pre-clinical data to clinic will be assessed in samples from HNSCC patients treated with an EphB4- EFNB2 inhibitor during a window trial. Project 2 investigates if dual inhibition of TGFβ/PD-L1 combined with radiation therapy (RT) induces in situ vaccination, reverses immune suppression, and overcomes RT resistance. It will translate its findings with a trial of the TGFβ/PD-L1 dual inhibitor M7824 combined with RT in locally recurrent and oligometastatic HNSCC patients. Project 3 will study mechanisms of protein elongation inhibition in HNSCC, identifying key proteins targeted by the novel inhibitor SVC112 (a drug discovered in Colorado that is nearing clinical testing), and translating our findings by testing the distribution and prognostic significance of its target (eEF2) in patient samples. It will use immune relevant models including syngeneic and humanized mice to study immune-dependent and –independent mechanisms of SVC112 and study if protein elongation inhibition impacts the tumor microenvironment and enhances RT in HNSCC. The developmental research program (DRP) is designed to attract current HNC researchers and researchers from other fields to conduct innovative research in all types of cancers arising from head and neck tissues. The career enhancement program (CEP) is designed to solicit junior researchers to develop research projects to transition into independent HNC researchers. We encourage underrepresented minority (URM) and people with disabilities to apply for DRP and CEP projects. The CO HNC SPORE also includes Biospecimen/Pathology, Data Science, and Administrative Cores. In sum, the CO HNC SPORE will solidify in-depth HNC translational research and expand our team of dedicated HNC researchers. These activities will improve the care spanning the entire spectrum of HNC treatment from improving cures to developing innovative palliation strategies for HNC patients.

项目概要，总体科罗拉多州 (CO) 头颈癌 (HNC) SPORE 的主要目标是推进转化研究提高 HNC 患者的生存率和生活质量至关重要。因为头部和颈部器官支持呼吸、营养和交流等关键功能，因此，HNC 会导致显着的发病率和死亡率。 CO HNC SPORE 利用了我们的优势。基础和临床科学方面的专业知识，并使用独特的模型系统来识别新的分子和细胞 HNC 发病机制可通过治疗干预来治疗所有由 HNC 引起的癌症类型头颈部解剖部位的三个项目涵盖了头颈部鳞状细胞的治疗范围。癌（HNSCC），包括与烟草相关和人乳头瘤病毒（HPV）相关的 HNSCC。项目1通过抑制免疫细胞之间的EphB4-EFNB2相互作用来研究新的免疫治疗机制它将测试肿瘤内皮屏障处的 EphB4-EFNB2 信号传导是否被阻断。阻碍 Tregs 和 TAM 渗透和促进癌症存活或抑制 Teff 功能的能力。临床前数据对临床的适用性将在接受 EphB4-治疗的 HNSCC 患者的样本中进行评估窗口试验期间的 EFNB2 抑制剂研究是否与 TGFβ/PD-L1 双重抑制相结合。放射治疗 (RT) 诱导原位疫苗接种、逆转免疫抑制并克服 RT 耐药性。它将通过 TGFβ/PD-L1 双重抑制剂 M7824 联合 RT 在局部试验中转化其发现项目 3 将研究复发性和寡转移性 HNSCC 患者的蛋白质延伸抑制机制。在 HNSCC 中，识别新型抑制剂 SVC112（一种在科罗拉多州发现的药物，即将进行临床测试），并通过测试分布和预后意义来转化我们的发现患者样本中的目标（eEF2）将使用免疫相关模型，包括同基因和人源化小鼠。研究 SVC112 的免疫依赖性和独立性机制，并研究蛋白质延伸抑制是否影响肿瘤微环境并增强 HNSCC 的 RT 发展研究计划 (DRP)。旨在吸引当前HNC研究人员和其他领域的研究人员进行创新研究职业发展计划 (CEP) 旨在治疗由头颈部组织引起的所有类型的癌症。招募初级研究人员开发研究项目，以转型为独立的 HNC 研究人员。鼓励代表性不足的少数族裔 (URM) 和残疾人申请 DRP 和 CEP 项目。 CO HNC SPORE 还包括生物样本/病理学、数据科学和管理核心。总之，CO HNC SPORE 将巩固深入的 HNC 转化研究并扩大我们的专业团队 HNC 研究人员的这些活动将改善 HNC 治疗的整个范围的护理。改善治疗方法，为 HNC 患者开发创新的姑息治疗策略。