Yale SPORE in Skin Cancer

耶鲁 SPORE 在皮肤癌中的应用

• 批准号: 10468760
• 负责人: MARCUS W BOSENBERG
• 金额: $ 231.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468760
• 关键词: Adaptive Immune System; Address; Agonist; Animal Model; Beds; Bioinformatics; Biological Assay; Biological Markers; Biology; Biometry; Biopsy; Blood Circulation; CSF1 gene; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Collaborations; DNA Damage; Death Rate; Development; Disease; Environment; Epigenetic Process; Event; Eye; Fostering; Funding; Future; Genetic; Goals; Human; Immune Evasion; Immune checkpoint inhibitor; Immune system; Immunobiology; Immunocompetent; Immunooncology; Immunotherapy; Incidence; Institution; Interdisciplinary Study; KDM5B gene; Lead; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Methods; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Outcome; PD-1 inhibitors; PD-1/PD-L1; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Prevention; Prevention therapy; Process; Program Development; Radiation induced damage; Regimen; Research; Research Personnel; Resistance; Resources; Sampling; Science; Series; Site; Skin Cancer; Sun Exposure; Sunscreening Agents; Systemic Therapy; T-Lymphocyte; Technology; Testing; Thinness; Translating; Translational Research; Treatment Protocols; Tumor-infiltrating immune cells; Ultraviolet Rays; Work; Yale Cancer Center; advanced disease; animal model development; anti-tumor immune response; base; bench to bedside; biomarker development; career; clinical application; clinically relevant; design; digital pathology; histone demethylase; immune checkpoint; improved; improved outcome; inhibitor; innovation; liquid biopsy; medical schools; melanocyte; melanoma; mortality; mouse model; nanoparticle; new technology; new therapeutic target; next generation; novel; novel strategies; novel therapeutics; predicting response; predictive marker; prevent; programmed cell death protein 1; programs; resistance mechanism; response biomarker; translational scientist; triplet state; tumor; ultraviolet damage

OVERALL: PROJECT SUMMARY The Yale SPORE in Skin Cancer (YSPORE), now in its second funding cycle, involves a broad range of projects and investigators with diverse expertise, whose goal is to decrease mortality from melanoma by developing methods to prevent the disease and treat patients once it metastasizes. YSPORE leans on the immense scientific and clinical strengths at Yale School of Medicine and Yale Cancer Center including immunobiology, genetics, epigenetics, quantitative sciences, immuno-oncology, nanoparticles, animal models, and digital pathology. YSPORE investigators have made major contributions in recent years to understanding the effects of ultraviolet damage on melanocytes, determining the molecular events that lead to melanoma progression and developing novel immune therapy approaches for melanoma patients with advanced disease. Recent advances in systemic therapies for advanced melanoma, particularly immune checkpoint inhibitors, that prolong survival, pose a new set of challenges for clinicians which will be addressed by the proposed research program. The YSPORE translational research team proposes to accomplish the objective of decreasing morbidity and mortality from skin cancer through five specific aims: Specific Aim 1: Develop novel bioadhesive sunscreens and triplet-state quenchers for prevention of melanoma and test them in pilot clinical trials; Specific Aim 2: Develop liquid biopsy approaches for melanomas that metastasize to sites that are difficult to biopsy. Liquid biopsies will then be studied in patients treated with PD-1 inhibitors to identify predictors of response and determine mechanisms of resistance; Specific Aim 3: Study novel drugs that target the epigenetic modifier KDM5, to enhance T cell infiltration in tumors that are unresponsive to immune checkpoint inhibitors; Specific Aim 4: Develop new approaches to overcoming resistance to PD-1 inhibitors by co-targeting the innate and adaptive immune systems; and Specific Aim 5: Develop new research directions to decrease mortality from melanoma and nurture the next generation of translational investigators focusing on skin cancer through a Developmental Research Program and a Career Enhancement Program. We propose three cores (Administrative Core, Biospecimen Core and Biostatistics and Bioinformatics Core) to support the projects, their clinical aims, mechanistic studies, and biomarker development for clinical application. The Projects and Cores are designed to be highly coordinated with the goal of maximizing resources and potential impact. New collaborations will be established during the funding period through the Developmental Research Program with the support of the Administrative Core. Collaborations with other institutions and skin cancer SPORE sites will be fostered by the Administrative Core. These coordinated efforts will enhance analysis of patient samples, use of cell cultures and animal models, and development of predictive biomarker assays. Our purpose is to translate the innovative approaches proposed here to clinical therapies for prevention and treatment of skin cancer.

总体而言：项目概要 耶鲁皮肤癌 SPORE (YSPORE) 目前处于第二个资助周期，涉及广泛的项目 以及具有不同专业知识的研究人员，他们的目标是通过开发降低黑色素瘤的死亡率 预防疾病和治疗转移后患者的方法。 YSPORE 依靠大量的科学知识 以及耶鲁大学医学院和耶鲁大学癌症中心的临床优势，包括免疫生物学、遗传学、 表观遗传学、定量科学、免疫肿瘤学、纳米粒子、动物模型和数字病理学。 近年来，YSPORE 研究人员在了解紫外线的影响方面做出了重大贡献 黑色素细胞损伤，确定导致黑色素瘤进展和发展的分子事件 针对晚期黑色素瘤患者的新型免疫治疗方法。系统性研究的最新进展 晚期黑色素瘤的治疗方法，特别是延长生存期的免疫检查点抑制剂，提出了新的治疗方法 拟议的研究计划将解决临床医生面临的一系列挑战。伊波雷 转化研究小组提出实现降低皮肤病发病率和死亡率的目标 通过五个具体目标来防治癌症： 具体目标 1：开发新型生物粘附防晒霜和三重态 用于预防黑色素瘤的猝灭剂并在试点临床试验中进行测试；具体目标 2：开发液体活检 针对转移至难以活检部位的黑色素瘤的方法。然后将进行液体活检 在接受 PD-1 抑制剂治疗的患者中进行研究，以确定反应的预测因子并确定其机制 反抗;具体目标 3：研究针对表观遗传修饰剂 KDM5 的新药，以增强 T 细胞 对免疫检查点抑制剂无反应的肿瘤浸润；具体目标 4：开发新产品 通过共同靶向先天免疫和适应性免疫来克服 PD-1 抑制剂耐药性的方法 系统；具体目标 5：开发新的研究方向以降低黑色素瘤和 通过发展培养专注于皮肤癌的下一代转化研究人员 研究计划和职业提升计划。我们提出三个核心（行政核心、 生物样本核心和生物统计学和生物信息学核心）支持项目及其临床目标， 机制研究和临床应用生物标志物开发。项目和核心的设计 与最大化资源和潜在影响的目标高度协调。新的合作将是 在资助期间通过发展研究计划在以下机构的支持下建立 行政核心。与其他机构和皮肤癌孢子站点的合作将由 行政核心。这些协调一致的努力将加强对患者样本的分析、细胞培养物的使用和 动物模型和预测生物标志物测定的开发。我们的目标是将创新成果转化为 本文提出了预防和治疗皮肤癌的临床疗法。