Colorado Head and Neck Cancer SPORE

项目总结，总体 科罗拉多州(CO)头颈部癌(HNC)孢子的主要目标是促进翻译研究 以提高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呼吸、营养和交流等关键功能， 因此，HNC可导致严重的发病率和死亡率。CO HNC孢子利用我们的 在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的发病机制可通过治疗干预措施来治疗所有类型的癌症 头部和颈部的解剖位置。三个项目涵盖了头颈部鳞状细胞的治疗范围 癌症(HNSCC)，包括与烟草相关和与人类乳头瘤病毒(HPV)相关的HNSCC。 项目1通过抑制EphB4-EFNB2之间的免疫相互作用研究新的免疫治疗机制 细胞和内皮细胞。它将测试是否在肿瘤内皮屏障阻断EphB4-EFNB2信号 阻碍Tregs和Tams的渗透和促进癌症生存或抑制Tef功能的能力。这个 临床前数据的临床适用性将在接受EphB4治疗的HNSCC患者的样本中进行评估。 在窗口试验期间使用EFNB2抑制剂。项目2调查转化生长因子β/PD-L1的双重抑制是否与 放射治疗(RT)诱导原位接种，逆转免疫抑制，克服RT耐药。 它将把他们的发现转化为转化生长因子β/PD-L1双重抑制剂M7824联合局部RT的试验 复发和少转移的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(一种在科罗拉多州发现的药物， 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 其靶标(EEF2)在患者样本中。它将使用免疫相关模型，包括同基因小鼠和人源化小鼠 研究SVC112的免疫依赖和非依赖机制以及是否抑制蛋白质的伸长 影响HNSCC的肿瘤微环境，增强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 在头颈部组织引起的所有类型的癌症中。职业提升计划(CEP)的设计 征集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 鼓励代表不足的少数群体(URM)和残疾人申请DRP和CEP项目。 CO HNC孢子还包括生物显微镜/病理学、数据科学和管理核心。在……里面 总而言之，CO HNC孢子将巩固深入的HNC翻译研究，并扩大我们的专业团队 HNC研究人员。这些活动将从以下方面改善HNC治疗的整个范围 改善治疗，为HNC患者制定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.