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: 10645058
• 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/10645058
• 关键词: Adjuvant; Aftercare; Biology; CDK4 gene; Cell Cycle Progression; Cell Cycle Regulation; Cell Survival; Cells; Clinical; Collaborations; Combined Modality Therapy; 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; Micrometastasis; Modeling; Molecular Profiling; Mutation; Neoplasm Metastasis; Ocular Melanoma; Oncogenic; Orphan; Oxidative Phosphorylation; Patients; Primary Neoplasm; Process; Publishing; Recurrence; Reporter; Reporting; Research; Residual Neoplasm; Residual state; Resistance; Retinoic Acid Receptor; Sampling; Schedule; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Agents; Transforming Growth Factor beta; Up-Regulation; Uveal Melanoma; advanced disease; antagonist; cancer cell; cancer type; cyclin-dependent kinase inhibitor 1B; 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; novel therapeutic intervention; pre-clinical; prevent; prognosis biomarker; receptor; response; synergism; targeted agent; targeted treatment; therapeutically effective; transcriptomics; treatment response; 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，随着这些突破，转移性黑色素瘤的临床进展迅速

项目成果

Prognostic Values of G-Protein Mutations in Metastatic Uveal Melanoma.

• DOI: 10.3390/cancers13225749
• 发表时间: 2021-11-17
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Terai M;Shimada A;Chervoneva I;Hulse L;Danielson M;Swensen J;Orloff M;Wedegaertner PB;Benovic JL;Aplin AE;Sato T
• 通讯作者: Sato T

The Latest on Uveal Melanoma Research and Clinical Trials: Updates from the Cure Ocular Melanoma (CURE OM) Science Meeting (2019).

• DOI: 10.1158/1078-0432.ccr-20-2536
• 发表时间: 2021-01-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Chua V;Mattei J;Han A;Johnston L;LiPira K;Selig SM;Carvajal RD;Aplin AE;Patel SP
• 通讯作者: Patel SP

Targeting cancer cell dormancy.

针对癌细胞休眠。

• DOI: 10.1038/s41568-023-00642-x
• 发表时间: 2024
• 期刊: Nature reviews. Cancer
• 作者: Agudo,Judith;Aguirre-Ghiso,JulioA;Bhatia,Mickie;Chodosh,LewisA;Correia,AnaLuísa;Klein,ChristophA
• 通讯作者: Klein,ChristophA