Colorado Head and Neck Cancer SPORE

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。 HNC 患者的最佳治疗至关重要 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 可能导致显着的发病率和死亡率。 CO HNC SPORE 利用我们的优势 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癌症类型 头部和颈部的解剖部位。三个项目覆盖头颈部鳞状细胞治疗谱 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 细胞和内皮。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。的 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。项目 2 研究 TGFβ/PD-L1 的双重抑制是否与 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 复发性和寡转移性 HNSCC 患者。项目3将研究蛋白质伸长抑制机制 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）。它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 发生于头颈部组织的所有类型的癌症。职业提升计划（CEP）的设计 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。我们 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。在 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。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。

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.