Mechanisms of uveal melanoma dormancy and targeted therapy tolerance

葡萄膜黑色素瘤休眠机制及靶向治疗耐受性

基本信息

批准号：
10226338
负责人：
Julio A. Aguirre-Ghiso
金额：
$ 47.83万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10226338
关键词：
Adjuvant Aftercare Biology CDK4 gene Cell Cycle Progression Cell Cycle Regulation Cell Survival Cells Clinical Clinical Data Collaborations Complement Complication Data Development Disease Distant Drug Combinations Drug Tolerance Drug resistance ERBB2 gene Epigenetic Process Estrogen receptor positive FDA approved Family Future GNAQ gene Genes Goals Growth Heterogeneity Human Immunotherapy In Vitro Institution Label Link Liver Malignant Neoplasms Mediating Melanoma Cell Metastatic Melanoma Metastatic Neoplasm to the Liver Modeling Molecular Profiling Mutation Neoplasm Metastasis Ocular Melanoma Oncogenic Orphan Oxidative Phosphorylation Patients Primary Neoplasm Process Prognostic Marker Publishing Recurrence Reporter Reporting Research Residual Tumors Residual state Resistance Retinoic Acid Receptor Sampling Schedule Signal Pathway Signal Transduction Site Testing Therapeutic Therapeutic Agents Up-Regulation Uveal Melanoma advanced disease base cancer cell cancer type design effective therapy gain of function guanine nucleotide binding protein inducible gene expression inhibitor/antagonist innovation insight knock-down liver development loss of function malignant breast neoplasm melanoma mutant neoplastic cell novel pre-clinical prevent response synergism targeted agent targeted treatment therapeutically effective therapy development transcriptomics treatment strategy tumor tumor initiation

项目摘要

The clinical landscape of metastatic melanoma has advanced rapidly since 2009 with the breakthroughs of targeted therapies and immunotherapy. These therapeutic agents are now moving into the adjuvant setting. A current unmet need is to understand the biology of melanoma that fail to respond to either targeted or immunotherapy in order to devise new treatment strategies. A paradigm for these non- responsive subsets is uveal/ocular melanoma. A further complication is that nearly 50% of uveal melanoma patients will ultimately develop advanced disease involving liver metastasis without recurrence at the primary site; however, there is often a lag period ranging from years to decades between primary tumor treatment and development of liver macro-metastasis. This observation highlights the clinical importance of early tumor cell dissemination (DTC) and dormancy at distant sites. We are studying the cellular mechanisms of tumor dormancy and tolerance to targeted inhibitors in uveal melanoma. We aim to identify mechanisms controlling dormancy in uveal melanoma disseminated tumor cells. Mechanistic insights will lead to novel targeting approaches; thus, we aim to provide pre- clinical data for new treatment combinations for uveal melanoma patients. Aberrant cell cycle regulation is a hallmark feature of cancer. In uveal melanoma, cell cycle progression is promoted through mutations in the guanine-nucleotide binding proteins, GNAQ and GNA11. Selective CDK4/6 inhibitors are FDA- approved in ER-positive/HER2-negative breast cancer but their use in uveal melanoma will require optimization of drug combinations and schedules. We aim to understand how to utilize CDK4/6 inhibitors in uveal melanoma and combine them with agents that target dormant cells and/or drug tolerant persisters. We aim to define the molecular signatures of these therapy-induced drug tolerant persisterp cells in metastatic uveal melanoma. In this multi-PI R01, synergy is provided by our established published and ongoing collaborations on altered signaling pathways, cellular dormancy, metastasis biology and response to targeted therapies. Our research expertise in dormancy and melanoma biology complement each other and link to clinical strengths at our institutions. Our studies will determine how dormancy and oncogenic signaling pathways dictate survival and quiescence of uveal melanoma DTCs and how to target them to prevent metastatic re-growth. We anticipate that our mechanistic insights into uveal melanoma DTCs and metastasis biology will form the basis for new treatment options that in the near future could result in more potent and durable therapy responses.

自 2009 年以来，随着突破性进展，转移性黑色素瘤的临床前景迅速发展靶向治疗和免疫治疗。这些治疗剂现在正转向佐剂环境。当前未满足的需求是了解黑色素瘤的生物学，这些黑色素瘤对任何一种都没有反应靶向或免疫疗法，以设计新的治疗策略。这些非的范例反应性亚群是葡萄膜/眼部黑色素瘤。另一个并发症是近 50% 的葡萄膜黑色素瘤患者最终将发展为涉及肝转移的晚期疾病，而无需进行任何治疗。原发部位复发；然而，往往存在数年至数十年的滞后期原发性肿瘤治疗与肝大转移发展之间的关系。这一观察强调了早期肿瘤细胞传播（DTC）和远距离休眠的临床重要性。我们正在研究葡萄膜中肿瘤休眠和对靶向抑制剂的耐受性的细胞机制黑色素瘤。我们的目标是确定控制播散性葡萄膜黑色素瘤休眠的机制肿瘤细胞。机制见解将带来新颖的靶向方法；因此，我们的目标是提供预葡萄膜黑色素瘤患者新治疗组合的临床数据。细胞周期调节异常是癌症的一个标志性特征。在葡萄膜黑色素瘤中，突变促进细胞周期进展存在于鸟嘌呤核苷酸结合蛋白 GNAQ 和 GNA11 中。选择性 CDK4/6 抑制剂经 FDA 批准批准用于 ER 阳性/HER2 阴性乳腺癌，但将其用于葡萄膜黑色素瘤需要优化药物组合和方案。我们的目标是了解如何利用 CDK4/6 抑制剂在葡萄膜黑色素瘤中，并将它们与针对休眠细胞和/或耐药细胞的药物结合起来坚持者。我们的目标是定义这些治疗诱导的耐药持久性的分子特征转移性葡萄膜黑色素瘤中的细胞。在这个多PI R01中，协同作用是由我们既定的已发表和正在进行的关于改变信号通路、细胞休眠、转移的合作生物学和对靶向治疗的反应。我们在休眠和黑色素瘤生物学方面的研究专业知识相互补充并与我们机构的临床优势相联系。我们的研究将决定如何休眠和致癌信号通路决定葡萄膜黑色素瘤 DTC 的存活和静止以及如何靶向它们以防止转移性再生长。我们预计我们的机制洞察葡萄膜黑色素瘤 DTC 和转移生物学将构成新治疗方案的基础在不久的将来可能会产生更有效和持久的治疗反应。