Functional and Therapeutic Significance of PLK4 in Melanoma

PLK4 在黑色素瘤中的功能和治疗意义

• 批准号: 10671687
• 负责人: Nihal Ahmad
• 金额: $ 53.66万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-25 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671687
• 关键词: Adverse effects; BRAF gene; Biogenesis; Breslow Thickness; CDK4 gene; Cadherins; Cell Cycle Progression; Cell Line; Cell division; Centrioles; Centrosome; Clinical; Clinical Management; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Cyclin D1; Dangerousness; Data; Development; Diagnostic; Disease Outcome; Epithelium; Failure; Fibronectins; Genetic Transcription; Genetically Engineered Mouse; Genomic Instability; Goals; Human; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Investigation; Knock-out; LOX gene; Lesion; Link; MEK inhibition; MEKs; Malignant - descriptor; Malignant Neoplasms; Mediating; Melanocytic nevus; Melanoma Cell; Mesenchymal; Modality; Modeling; Mutation; Neoplasm Metastasis; Neoplasms; New Drug Approvals; Oncogenic; Outcome; PET/CT scan; PI3K/AKT; PLK1 gene; Pathway interactions; Patients; Phosphotransferases; Play; Primary Neoplasm; Protein-Serine-Threonine Kinases; Proteins; Publishing; Ras/Raf; Recurrence; Research; Resistance; Resistance development; Role; Sampling; Serine; Signal Transduction; Skin Cancer; Snails; Specimen; Staging; System; Therapeutic; Time; Tissue Microarray; Transgenic Mice; UV induced; Ultraviolet Rays; Vimentin; X-Ray Computed Tomography; Xenograft procedure; cancer cell; carcinogenesis; cell motility; clinically relevant; driver mutation; druggable target; epidemiologic data; epithelial to mesenchymal transition; experimental study; genomic data; improved; in vivo; inhibitor; knock-down; liquid crystal polymer; melanocyte; melanoma; mortality; mouse model; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; prognostic; prognostic value; response; small molecule; tumor growth; tumor progression

SUMMARY: The objective of this study is to determine if the polo-like kinase 4 (PLK4) along with other melanoma driver pathways, is a therapeutically actionable druggable target for melanoma management, and what are the mechanisms and interacting partners of PLK4, during melanocytic transformation and neoplastic progression. Melanoma is a clinically challenging skin cancer, if not diagnosed early. Epidemiological and genomic data suggest that BRAFV600E mutations may be the initiating lesion in melanocytic nevi; however, these mutations alone are not sufficient for malignant transformation. Ultraviolet radiation (UVR) and activation of other oncogenic pathways are known to contribute to the neoplastic progression of melanocytes. In the recent past, the treatment landscape for advanced melanoma management has seen dramatic changes with the approval of new drugs such as BRAF inhibitors as well as immune-checkpoint inhibitors. However, these treatments are linked with acquired resistance occurring in nearly 50% of patients. Therefore, novel mechanism-based therapeutic approaches are needed for effective management of this dreaded neoplasm. Based on limited number of recent studies, PLK4 is being considered as a potential druggable target for certain cancers. PLK4 inhibition has been shown to cause a failure of centriole and centrosome duplication, whereas its overexpression results in excess centriole formation, which are sufficient to drive centrosome amplification (CA) and genome instability that is linked to carcinogenesis. A recent study has suggested a role of PLK4 in epithelial-mesenchymal transition (EMT) via modulating PI3K/AKT pathway. We recently demonstrated that PLK4 is significantly overexpressed in melanoma, and small molecule PLK4 inhibition resulted in a significant anti-proliferative response in multiple melanoma cell lines [Mol Cancer Res, 2018]. Our preliminary data has shown that PLK4 CRISPR K/O A375 melanoma cells show significantly decreased tumor growth in melanoma xenografts suggesting an important role of PLK4 in melanoma. We also found that combined inhibition of PLK4 with BRAF and MEK inhibition exerted synergistic antiproliferative effect in melanoma cells. In this study, we propose to challenge a hypothesis that PLK4 signaling, together with other driver pathways of melanocytic transformation and neoplastic progression, will provide therapeutically-actionable novel co-targeting approaches, for melanoma management. Three aims are proposed to; 1) determine the association between PLK4 and other driver pathways of melanocytic transformation and neoplastic progression ex vivo; 2) determine the functional and mechanistic significance of PLK4 in melanoma progression and metastasis in vivo in a variety of human-relevant genetically engineered mouse models; 3) determine the therapeutic significance of PLK4 inhibition, alone and in combination with other promising target-based anti-melanoma modalities in vivo. We expect that our study will establish the exact role of PLK4 in melanoma, and its diagnostic/prognostic as well as therapeutic significance in this neoplasm.

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