Yale SPORE in Skin Cancer

总体情况：项目总结 耶鲁大学皮肤癌孢子项目(YSPORE)目前正处于第二个资助周期，涉及范围广泛的项目 以及拥有不同专业知识的研究人员，他们的目标是通过开发 方法预防疾病，一旦转移就治疗。YSPORE依赖于巨大的科学 以及耶鲁医学院和耶鲁癌症中心的临床优势，包括免疫生物学、遗传学、 表观遗传学、量化科学、免疫肿瘤学、纳米粒子、动物模型和数字病理学。 近年来，YSPORE的研究人员在了解紫外线的影响方面做出了重大贡献 损害黑素细胞，确定导致黑色素瘤进展和发展的分子事件 晚期黑色素瘤患者的新免疫治疗方法。全身性的最新进展 晚期黑色素瘤的治疗方法，特别是免疫检查点抑制剂，延长了生存时间，构成了一种新的 临床医生面临的一系列挑战，这些挑战将由拟议的研究计划解决。YSPORE 翻译研究小组建议实现降低皮肤发病率和死亡率的目标 癌症通过五个特定目标：特定目标1：开发新型生物粘附性防晒霜和三联体 用于黑色素瘤预防的猝灭剂并在试点临床试验中进行测试；特定目标2：发展液体活检 转移到难以活检的部位的黑色素瘤的治疗方法。液体活组织检查将会被 在接受PD-1抑制剂治疗的患者中进行研究，以确定应答的预测因素并确定其机制 抗药性；具体目标3：研究针对表观遗传修饰物KDM5的新药，以增强T细胞 对免疫检查点抑制剂无效的肿瘤中的渗透；具体目标4：开发新的 共靶向先天免疫和获得性免疫克服PD-1抑制剂耐药性的途径 具体目标5：开发新的研究方向，以降低黑色素瘤死亡率和 通过发展性研究培养关注皮肤癌的下一代翻译研究人员 研究计划和职业提升计划。我们提出了三个核心(管理核心、 Biosecimen核心和生物统计学和生物信息学核心)，以支持项目、其临床目标、 机制研究，以及临床应用的生物标记物开发。设计了项目和核心 与最大化资源和潜在影响的目标高度协调。新的协作将是 通过发展研究方案在资助期间建立，并得到 管理核心。与其他机构和皮肤癌孢子点的合作将由 管理核心。这些协调努力将加强对患者样本的分析，使用细胞培养和 动物模型，以及预测性生物标志物分析的发展。我们的宗旨是将创新的 本文提出了预防和治疗皮肤癌的临床治疗方法。

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.