Colorado Head and Neck Cancer SPORE

科罗拉多头颈癌孢子

• 批准号: 10477441
• 负责人: Antonio Jimeno
• 金额: $ 182.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/10477441
• 关键词: Address; Anatomy; Basic Science; Biological Models; Biopsy; Breathing; Cancer Model; Caring; Cell Survival; Cell physiology; Cells; Clinic; Clinical Data; Clinical Sciences; Clinical Trials; Colorado; Cyclin D1; Data; Data Science; Development; Disabled Persons; Discipline; Endothelium; Enrollment; 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; 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; Pharmacology; Phase; Postdoctoral Fellow; Prognostic Marker; Proteins; Quality of life; Radiation therapy; Recurrence; Regimen; Regulatory T-Lymphocyte; Research; Research Personnel; Research Project Grants; Resistance; Sampling; Signal Transduction; Sum; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tobacco; Transforming Growth Factor beta; Translating; Translational Research; Translations; Treatment Efficacy; Tumor-associated macrophages; Underrepresented Minority; United States National Institutes of Health; Vascular Endothelial Cell; 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; patient derived xenograft model; phase I trial; pre-clinical; predictive marker; prognostic; prognostic significance; programmed cell death ligand 1; programs; recruit; research and development; research clinical testing; targeted treatment; therapeutic target; therapy development; translational cancer research; tumor; tumor microenvironment

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.

项目摘要，总体 科罗拉多州（CO）头颈癌（HNC）孢子的主要目标是推进翻译研究 改善HNC患者的生存和生活质量。 HNC患者的最佳治疗至关重要 因为头部和颈部器官支持关键功能，例如呼吸，滋养和交流，所以 因此，HNC可以导致明显的发病率和死亡率。 Co HNC孢子利用了我们 基础科学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型分子和细胞 HNC发病机理的机制可通过理论干预措施来治疗所有癌症类型 头部和颈部解剖部位。三个项目涵盖了头和颈部鳞状细胞的治疗范围 癌（HNSCC），包括与烟草相关的和人乳头瘤病毒（HPV）相关的HNSCC。 项目1通过抑制免疫力之间的EPHB4-EFNB2相互作用来研究新型免疫疗法机制 细胞和内皮。它将测试是否在肿瘤内皮屏障处封锁EPHB4-EFNB2信号传导 阻碍Tregs和TAMS的浸润和促进癌症存活或抑制TEFF功能的能力。这 临床前数据对诊所的适用性将在接受EPHB4-治疗的HNSCC患者的样本中评估 窗户试验期间的EFNB2抑制剂。项目2研究TGFβ/PD-L1的双重抑制是否与 放射疗法（RT）可诱导原位疫苗接种，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与RT合并的TGFβ/PD-L1双重抑制剂的试验来转化其发现。 复发性和寡聚性HNSCC患者。项目3将研究蛋白质伸长抑制的机制 在HNSCC中，识别新型抑制剂SVC112靶向的关键蛋白（在科罗拉多州发现的药物 即将接近临床测试），并通过测试分布和预后意义来翻译我们的发现 它的靶标（EEF2）在患者样品中。它将使用包括同烯和人源化小鼠在内的免疫呈现模型 研究SVC112的免疫依赖性和非依赖性机制，并研究蛋白质伸长抑制 影响肿瘤微环境并增强HNSCC的RT。发展研究计划（DRP） 旨在吸引当前的HNC研究人员和其他领域的研究人员进行创新研究 在所有类型的癌症中，头部和颈部组织产生。职业增强计划（CEP）的设计 邀请初级研究人员开发研究项目，以过渡到独立的HNC研究人员。我们 鼓励代表性不足的少数民族（URM）和残疾人申请DRP和CEP项目。 CO HNC孢子还包括生物镜/病理学，数据科学和行政核心。在 总而言之，HNC孢子将巩固深入的HNC翻译研究，并扩大我们的专用团队 HNC研究人员。这些活动将改善跨越HNC治疗整个HNC治疗的护理 改善为HNC患者制定创新抑制策略的治疗方法。