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.

概括： 这项研究的目的是确定polo样激酶4（PLK4）以及其他黑色素瘤驱动器是否 途径，是用于黑色素瘤治疗的治疗可操作的可药物靶标，什么是 在黑素细胞转化和肿瘤进展过程中，PLK4的机理和相互作用的伴侣。 黑色素瘤是一种临床上具有挑战性的皮肤癌，即使没有早期诊断。流行病学和基因组数据 表明BRAFV600E突变可能是黑素核NEVI的启动病变。但是，这些突变 仅凭恶性转化就不够。紫外线辐射（UVR）和其他 已知致癌途径有助于黑素细胞的肿瘤进展。在最近的过去， 经过批准，用于高级黑色素瘤管理的治疗景观发生了巨大变化 诸如BRAF抑制剂以及免疫检查点抑制剂之类的新药。但是，这些治疗方法是 与近50％的患者发生的获得的抗药性有关。因此，基于新颖的机制 有效地管理这种可怕的肿瘤需要治疗方法。基于有限 最近的研究数量，PLK4被认为是某些癌症的潜在可药物靶标。 PLK4 已显示抑制作用会导致中心和中心体重复的失败，而其 过表达导致过量的中心形成，足以驱动中心体扩增 （CA）和基因组不稳定性与致癌作用有关。最近的一项研究表明，PLK4在 通过调节PI3K/AKT途径，上皮 - 间质转变（EMT）。我们最近证明了 PLK4在黑色素瘤中显着过表达，小分子PLK4抑制作用导致显着 多种黑色素瘤细胞系中的抗增殖反应[Mol Cancer Res，2018]。我们的初步数据 表明PLK4 CRISPR K/O A375黑色素瘤细胞在黑色素瘤中显示出明显降低的肿瘤生长 异种移植物表明PLK4在黑色素瘤中的重要作用。我们还发现PLK4的合并抑制作用 BRAF和MEK抑制作用在黑色素瘤细胞中发挥协同抗增殖作用。在这项研究中，我们 提出挑战PLK4信号传导以及其他黑色素细胞驱动器途径的假设 转化和肿瘤进展将提供可治疗性的新型共同目标 方法，用于黑色素瘤管理。提出了三个目标： 1）确定 PLK4和其他黑色素转化和肿瘤进展的驱动力途径； 2） 确定PLK4在黑色素瘤进展和转移中的功能和机械意义 体内各种与人相关的基因工程小鼠模型； 3）确定治疗性 PLK4抑制的重要性，单独并与其他有前途的基于目标的抗黑色素瘤结合 体内模态。我们希望我们的研究将确定PLK4在黑色素瘤中的确切作用，及其 该肿瘤中的诊断/预后和治疗意义。