The University of Texas MD Anderson Cancer Center SPORE in Melanoma

总体：项目摘要/摘要 黑色素瘤是皮肤癌中最致命的一种，发病率和死亡率呈上升趋势，并持续5年 转移性疾病患者存活率不到20%。几个最近具有里程碑意义的基因组和 免疫学研究对脑血管病的发病机制、驱动因素和调节因素产生了重要的新见解。 这种疾病，转化为对转移性癌症患者的靶向治疗和免疫治疗的批准 疾病。虽然靶向治疗取得了很高的应答率，但它们通常是暂时的；同样， 免疫疗法带来戏剧性的、长期的、完全的反应，但只在一小部分患者和 通常有严重的毒副作用。尽管已经取得了进展，但在以下方面仍然存在几个关键挑战 最大化免疫治疗的临床益处：1)对免疫治疗的标志物和机制知之甚少 对免疫治疗的抵抗力，以及缺乏克服它们的有效策略；2)经验有限或 中枢神经系统受累患者的疗效、常见转移部位和死亡原因 黑色素瘤和其他癌症；以及3)单剂免疫疗法对以下患者没有任何好处 非皮肤黑色素瘤，尤其是葡萄膜黑色素瘤亚型。这种孢子的中心假说 建议对晚期糖尿病患者的免疫和分子特征进行综合分析 黑色素瘤将提高我们对免疫治疗的反应和抵抗力的理解，并导致 更有效的治疗方法。为了验证这一假设，我们将关注以下最关键的未满足需求 黑色素瘤患者，建立在现有免疫治疗策略的基础上，开发我们自己的新技术 通过追求以下具体目标来确定更有效的治疗选择的概念： ·通过抑制PTEN中的PI3K通路来解决对PD-1免疫检查点抑制剂的耐药性- 无转移性黑色素瘤患者(项目1)。 ·确定鞘内注射nivolumab阻断PD-1治疗转移性肿瘤的临床有效性 患有软脑膜疾病的黑色素瘤患者(项目2)。 ·评估葡萄膜黑色素瘤的新治疗策略，该策略使用过继细胞疗法来靶向 黑素体转运蛋白SLC45A2的免疫原性表位(项目3)。 三个核心(管理核心、临床数据库、组织资源和翻译病理学核心 [核心2]和生物统计和生物信息学核心[核心3])提供专门的服务来支持我们的孢子 调查人员及其拟议的研究报告。这三个项目和核心以及我们的 发展研究和职业提升计划将全面打击关键 与这些致命的黑色素瘤表现作斗争的患者的未得到满足的需求，并为其他 治疗选择有限的癌症。

Overall: Project Summary/Abstract Melanoma is the deadliest form of skin cancer, with an increasing incidence and mortality, and a 5-year survival rate less than 20% for patients with metastatic disease. Several recent landmark genomic and immunologic studies have generated important new insights into the pathogenesis, drivers, and regulators of this disease, translating into the approval of both targeted and immune therapies for patients with metastatic disease. While targeted therapies have achieved high response rates, they are generally transient; likewise, immunotherapies bring about dramatic, long-term, complete responses but only in a subset of patients and often with serious toxicities. Despite the progress that has been made, several key challenges remain to maximizing the clinical benefit of immunotherapy: 1) poorly understood markers and mechanisms of resistance to immunotherapy, and a lack of effective strategies to overcome them; 2) limited experience or efficacy in patients with central nervous system involvement, a common metastatic site and cause of death for melanoma and other cancers; and 3) lack of any benefit from single-agent immunotherapies in patients with non-cutaneous melanomas, particularly the uveal melanoma subtype. The central hypothesis of this SPORE proposal is that an integrated analysis of immune and molecular features in patients with advanced melanoma will improve our understanding of response and resistance to immunotherapy, and lead to more effective treatments. To test this hypothesis, we will focus on the most critical unmet needs of melanoma patients, building on current immunotherapeutic strategies and developing our own novel concepts to identify more effective treatment options by pursuing the following specific aims: • Address resistance to the PD-1 immune checkpoint inhibitor through inhibition of the PI3K pathway in PTEN- null metastatic melanoma patients (Project 1). • Determine the clinical utility of PD-1 blockade using nivolumab administered intrathecally in metastatic melanoma patients with leptomeningeal disease (Project 2). • Evaluate a new therapeutic strategy for uveal melanoma that uses adoptive cell therapy to target an immunogenic epitope of melanosomal transport protein SLC45A2 (Project 3). Three cores (Administrative Core, Clinical Database, Tissue Resource, and Translational Pathology Core [Core 2] and Biostatistics and Bioinformatics Core [Core 3]) provide specialized services to support our SPORE investigators and their proposed research studies. Together, these three projects and cores and our Developmental Research and Career Enhancement Programs will provide a comprehensive attack on critical unmet needs for patients battling these deadly manifestations of melanoma, and pave the way for other cancers with limited therapeutic options.