The University of Texas MD Anderson Cancer Center SPORE in Melanoma

德克萨斯大学 MD 安德森癌症中心 SPORE 黑色素瘤

• 批准号: 10683940
• 负责人: Michael Davies
• 金额: $ 207.04万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683940
• 关键词: Address; Adjuvant; Adoptive Cell Transfers; Adult; Affinity; Bioinformatics; Biometry; Carrier Proteins; Cause of Death; Central Nervous System; Cessation of life; Clinical; Clinical Research; Clinical Trials; Common Neoplasm; Communication; Community Health; Cutaneous Melanoma; Cytotoxic T-Lymphocytes; Data Analyses; Development; Disease; Distant Metastasis; Ensure; Epitopes; Experimental Designs; Eye Neoplasms; Faculty; Funding; Future; Genomics; Goals; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunology; Immunotherapeutic agent; Immunotherapy; In complete remission; Incidence; Investigation; Knowledge; Left; Leptomeninges; Malignant Neoplasms; Melanosomes; Mentors; Metastatic Melanoma; Metastatic Neoplasm to the Central Nervous System; Molecular; Molecular Biology; Nivolumab; Non-Cutaneous Melanoma; Outcome; PD-1 blockade; PIK3CG gene; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Patients; Pilot Projects; Population; Refractory; Research; Research Personnel; Resistance; Resources; Safety; Service provision; Services; Site; Skin Cancer; Survival Rate; Testing; Therapeutic; Toxic effect; Translating; Translational Research; Treatment Failure; University of Texas M D Anderson Cancer Center; Uveal Melanoma; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; burden of illness; career; clinical database; clinical investigation; combinatorial; data sharing; effective therapy; experience; global health; immunogenic; improved; insight; meetings; melanoma; microbiome; mortality; multidisciplinary; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient subsets; programmed cell death protein 1; programs; research study; resistance mechanism; response; targeted treatment; therapy resistant; tissue resource; treatment site; treatment strategy; tumor

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.

总体：项目总结/摘要 黑色素瘤是皮肤癌中最致命的形式，其发病率和死亡率不断增加，并且5年 转移性疾病患者的生存率低于20%。最近几个里程碑式的基因组和 免疫学研究已经产生了重要的新见解的发病机制，驱动程序，和调节器， 这种疾病，转化为对转移性乳腺癌患者的靶向和免疫治疗的批准， 疾病虽然靶向治疗已经实现了高响应率，但它们通常是短暂的;同样， 免疫疗法带来显著的、长期的、完全的反应，但仅在一部分患者中， 通常具有严重的毒性。尽管取得了进展，但仍存在一些关键挑战， 最大化免疫疗法的临床益处：1）对免疫疗法的标记物和机制知之甚少， 对免疫疗法的抵抗，缺乏有效的策略来克服它们; 2）经验有限， 在中枢神经系统受累患者中的疗效，中枢神经系统受累是常见的转移部位和死亡原因， 黑色素瘤和其他癌症;以及3）在患有恶性黑色素瘤和其他癌症的患者中缺乏来自单一药剂免疫疗法的任何益处。 非皮肤黑色素瘤，特别是葡萄膜黑色素瘤亚型。这个孢子的中心假设 建议对晚期乳腺癌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疗法的反应和抵抗的理解，并导致 更有效的治疗。为了验证这一假设，我们将重点关注最关键的未满足的需求， 黑色素瘤患者，建立在当前的免疫策略和开发我们自己的新的 通过实现以下具体目标，确定更有效的治疗方案的概念： ·通过抑制PTEN中的PI 3 K途径解决对PD-1免疫检查点抑制剂的抗性。 无效转移性黑色素瘤患者（项目1）。 ·确定使用在转移性肿瘤患者中鞘内施用的纳武单抗的PD-1阻断的临床效用 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葡萄膜黑色素瘤。 黑素体转运蛋白SLC 45 A2的免疫原性表位（项目3）。 三个核心（管理核心、临床数据库、组织资源和转化病理学核心 [Core 2]和生物统计学和生物信息学核心[核心3]）提供专业服务，以支持我们的SPORE 研究人员及其研究计划。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提供一个全面的攻击关键 为与这些致命的黑色素瘤表现作斗争的患者提供未满足的需求，并为其他治疗铺平道路。 治疗选择有限的癌症。

项目成果

Efficacy of Immune Checkpoint Inhibitors for the Treatment of Advanced Melanoma in Patients with Concomitant Chronic Lymphocytic Leukemia.

• DOI: 10.1016/j.annonc.2023.06.007
• 发表时间: 2023-07
• 期刊: Annals of oncology : official journal of the European Society for Medical Oncology
• 作者: S. Cass;J. Tobin;Y. D. Seo;G. Gener-Ricos;E. Keung;E. Burton;M. Davies;J. McQuade;A. Lazar;R. Mason;M. Millward;S. Sandhu;C. Khoo;L. Warburton;V. Guerra;A. Haydon;H. Dearden;A. Menzies;M. Carlino;J. Smith;P. Mollee;M. Burgess;S. Mapp;C. Keane;V. Atkinson;S. Parikh;S. Markovic;W. Ding;T. Call;P. Hampel;G. Long;J. Wargo;A. Ferrajoli

Mitotic rate in primary cutaneous melanoma: Cell division matters.

原发性皮肤黑色素瘤的有丝分裂率：细胞分裂很重要。

• DOI: 10.1002/cncr.34825
• 发表时间: 2023
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Gershenwald,JeffreyE

MULTIPLATFORM ANALYSIS OF INTRATUMORAL PTEN HETEROGENEITY IN MELANOMA.

• DOI: 10.1016/j.jid.2023.01.034
• 发表时间: 2023-03
• 期刊: The Journal of investigative dermatology
• 作者: Sharmeen Chagani;M. P. de Macedo;F. Carapeto;Feng Wang;D. Marzese;K. Wani;L. Haydu;W. Peng;Giang T Ong;S. Warren;J. Beechem;D. Hoon;G. Mills;M. Tetzlaff;A. Lazar;L. Kwong;M. Davies

Neoadjuvant relatlimab and nivolumab in resectable melanoma.

• DOI: 10.1038/s41586-022-05368-8
• 发表时间: 2022-11
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Amaria, Rodabe N.;Postow, Michael;Burton, Elizabeth M.;Tezlaff, Michael T.;Ross, Merrick, I;Torres-Cabala, Carlos;Glitza, Isabella C.;Duan, Fei;Milton, Denai R.;Busam, Klaus;Simpson, Lauren;McQuade, Jennifer L.;Wong, Michael K.;Gershenwald, Jeffrey E.;Lee, Jeffrey E.;Goepfert, Ryan P.;Keung, Emily Z.;Fisher, Sarah B.;Betof-Warner, Allison;Shoushtari, Alexander N.;Callahan, Margaret;Coit, Daniel;Bartlett, Edmund K.;Bello, Danielle;Momtaz, Parisa;Nicholas, Courtney;Gu, Aidi;Zhang, Xuejun;Korivi, Brinda Rao;Patnana, Madhavi;Patel, Sapna P.;Diab, Adi;Lucci, Anthony;Prieto, Victor G.;Davies, Michael A.;Allison, James P.;Sharma, Padmanee;Wargo, Jennifer A.;Ariyan, Charlotte;Tawbi, Hussein A.
• 通讯作者: Tawbi, Hussein A.

Body mass index and survival after cancer diagnosis: A pan-cancer cohort study of 114 430 patients with cancer.

• DOI: 10.1016/j.xinn.2022.100344
• 发表时间: 2022-11-08
• 期刊: INNOVATION
• 影响因子: 32.1
• 作者: Tu, Huakang;McQuade, Jennifer L.;Davies, Michael A.;Huang, Maosheng;Xie, Kunlin;Ye, Yuanqing;Chow, Wong-Ho;Rodriguez, Alma;Wu, Xifeng;Davies, Michael A.;Huang, Maosheng;Xie, Kunlin;Ye, Yuanqing;Rodriguez, Alma
• 通讯作者: Rodriguez, Alma