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)现已进入第三个资助周期，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新的 一旦转移就治疗患者的药物和方案，并开发预测生物标记物来选择患者 寻找最佳的治疗方案。YSPORE依靠耶鲁学院强大的科学和临床优势 医学和耶鲁癌症中心包括免疫生物学，遗传学，表观遗传学，定量科学， 免疫肿瘤学、动物模型和数字病理学。YSPORE调查人员做出了重大贡献 近年来致力于为晚期黑色素瘤患者开发改进的免疫治疗方法 疾病和新的单细胞肿瘤分析平台。晚期黑色素瘤的系统治疗进展， 尤其是延长生存的免疫检查点抑制剂，对临床医生提出了一系列新的挑战， 将由拟议的研究计划解决，因为我们努力提高所有人的长期存活率 黑色素瘤患者。YSPORE翻译研究团队建议实现以下目标 通过四个具体目标降低皮肤癌的发病率和死亡率：具体目标1：开发新的 通过共同靶向先天免疫系统和获得性免疫系统增强PD-1抑制剂活性的方法 免疫检查点抑制物幼稚患者；特定目标2：研究靶向表观遗传修饰物的新药 KDM5B，上调内源性逆转录因子，增强T细胞在无反应肿瘤中的渗透 或对免疫检查点抑制剂反应不佳；具体目标3：研究新的细胞因子以克服 抗PD-1进展的黑色素瘤患者对免疫检查点抑制剂的抵抗力；以及 具体目标4：开发新的研究方向以降低黑色素瘤的死亡率并培育下一个 通过发展研究计划产生关注皮肤癌的转化型研究人员 和一个职业提升计划。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、机制研究和 临床应用生物标记物的开发。这些项目和核心被设计成高度协调的 以最大限度地利用资源和潜在影响为目标。新的合作伙伴关系将在 在行政核心的支持下，通过发展研究方案提供资金。 行政核心将促进与其他机构和皮肤癌孢子点的合作。 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 生物标志物预测性分析方法的发展。我们的目的是将提出的创新方法 下面是晚期皮肤癌的临床治疗方法。

OVERALL: PROJECT SUMMARY The Yale SPORE in Skin Cancer (YSPORE), now in its third funding cycle, involves a broad range of projects and investigators with diverse expertise, whose goal is to decrease mortality from melanoma by developing novel drugs and regimens to treat patients once it metastasizes and develop predictive biomarkers to select patients for the optimal treatment regimen. 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, animal models, and digital pathology. YSPORE investigators have made major contributions in recent years to developing improved immune therapy approaches for melanoma patients with advanced disease and novel single cell tumor profiling platforms. 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, as we strive to increase the long term survival for all melanoma patients. The YSPORE translational research team proposes to accomplish the objective of decreasing morbidity and mortality from skin cancer through four specific aims: Specific Aim 1: Develop new approaches to enhancing activity of PD-1 inhibitors by co-targeting the innate and adaptive immune systems in immune checkpoint inhibitor naïve patients; Specific Aim 2: Study novel drugs that target the epigenetic modifier KDM5B, to upregulate endogenous retroelements and enhance T cell infiltration in tumors that are unresponsive or poorly responsive to immune checkpoint inhibitors; Specific Aim 3: Study novel cytokines to overcome resistance to immune checkpoint inhibitors in patients whose melanoma has progressed on anti-PD-1; and Specific Aim 4: 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 treatment of advanced skin cancer.