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

• 批准号: 10414811
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 47.26万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 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/10414811
• 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; 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; antagonist; base; cancer cell; cancer type; design; effective therapy; gain of function; guanine nucleotide binding protein; inducible gene expression; inhibitor; inhibitor therapy; innovation; insight; knock-down; liver development; loss of function; malignant breast neoplasm; melanoma; mutant; neoplastic cell; novel; pre-clinical; prevent; prognosis biomarker; response; synergism; targeted agent; targeted treatment; therapeutically effective; therapy development; transcriptomics; treatment response; treatment strategy; tumor; tumor initiation

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，转移性黑色素瘤的临床状况随着这些突破而迅速发展。 靶向治疗和免疫治疗。这些治疗剂现在正在进入佐剂 设置.目前未满足的需求是了解黑色素瘤的生物学， 靶向治疗或免疫治疗，以设计新的治疗策略。这些非- 反应性子集是葡萄膜/眼黑素瘤。另一个并发症是近50%的葡萄膜 黑色素瘤患者将最终发展为涉及肝转移的晚期疾病， 在原发部位复发;然而，通常有几年到几十年的滞后期 原发性肿瘤治疗和肝脏大转移之间的关系。该观察结果 强调了早期肿瘤细胞播散（DTC）和远端休眠的临床重要性。 我们正在研究肿瘤休眠的细胞机制和葡萄膜对靶向抑制剂的耐受性 黑素瘤我们的目的是确定控制葡萄膜黑色素瘤播散性休眠的机制， 肿瘤细胞机制的见解将导致新的靶向方法，因此，我们的目标是提供前， 葡萄膜黑色素瘤患者新治疗组合的临床数据。细胞周期异常调控 是癌症的标志性特征在葡萄膜黑色素瘤中，细胞周期进程通过突变促进 鸟嘌呤核苷酸结合蛋白GNAQ和GNA 11。选择性CDK 4/6抑制剂是FDA- 它们被批准用于ER阳性/HER 2阴性乳腺癌，但它们用于葡萄膜黑色素瘤需要 优化药物组合和时间表。我们的目标是了解如何利用CDK 4/6抑制剂 并将它们与靶向休眠细胞和/或耐药细胞的药剂联合收割机组合 顽固分子我们的目标是确定这些治疗诱导的耐药持续存在的分子特征， 转移性葡萄膜黑色素瘤中的细胞。在这种多PI R 01中，协同作用由我们建立的 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长 相互补充，并与我们机构的临床优势联系起来。我们的研究将决定 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，我们的机械见解， 葡萄膜黑色素瘤DTCs和转移生物学将构成新治疗选择的基础 在不久的将来，可能会产生更有效和持久的治疗反应。