Functional and Therapeutic Significance of PLK4 in Melanoma

PLK4 在黑色素瘤中的功能和治疗意义

基本信息

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
项目类别：
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

项目摘要

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：本研究的目的是确定 Polo 样激酶 4 (PLK4) 是否与其他黑色素瘤驱动因素一起途径，是黑色素瘤管理的治疗上可行的药物靶点，以及什么是 PLK4 在黑素细胞转化和肿瘤进展过程中的机制和相互作用伙伴。如果不及早诊断，黑色素瘤是一种临床上具有挑战性的皮肤癌。流行病学和基因组数据表明 BRAFV600E 突变可能是黑素细胞痣的起始病变；然而，这些突变单独的作用不足以导致恶性转化。紫外线辐射 (UVR) 和其他物质的激活已知致癌途径有助于黑素细胞的肿瘤进展。在不久的过去，随着批准，先进黑色素瘤管理的治疗格局发生了巨大变化 BRAF抑制剂和免疫检查点抑制剂等新药的研发。然而，这些治疗方法都是与近 50% 患者发生的获得性耐药有关。因此，基于新机制的需要有效治疗这种可怕肿瘤的治疗方法。基于有限最近的许多研究表明，PLK4 被认为是某些癌症的潜在药物靶标。 PLK4 抑制已被证明会导致中心粒和中心体复制失败，而其过度表达导致过量中心粒形成，这足以驱动中心体扩增（CA）和与致癌相关的基因组不稳定性。最近的一项研究表明 PLK4 在通过调节 PI3K/AKT 通路实现上皮间质转化 (EMT)。我们最近证明了 PLK4 在黑色素瘤中显着过表达，小分子 PLK4 抑制导致显着的多种黑色素瘤细胞系的抗增殖反应 [Mol Cancer Res, 2018]。我们的初步数据有显示 PLK4 CRISPR K/O A375 黑色素瘤细胞显示黑色素瘤的肿瘤生长显着减少异种移植表明 PLK4 在黑色素瘤中发挥重要作用。我们还发现 PLK4 的联合抑制 BRAF 和 MEK 抑制在黑色素瘤细胞中发挥协同抗增殖作用。在这项研究中，我们提出质疑 PLK4 信号传导以及黑素细胞的其他驱动途径的假设转化和肿瘤进展，将提供治疗上可行的新型共同靶向方法，用于黑色素瘤管理。提出了三个目标； 1）确定之间的关联 PLK4 和离体黑素细胞转化和肿瘤进展的其他驱动途径； 2）确定 PLK4 在黑色素瘤进展和转移中的功能和机制意义多种与人类相关的基因工程小鼠模型体内； 3）确定治疗方案单独或与其他有前景的基于靶点的抗黑色素瘤药物联合使用 PLK4 抑制的意义体内方式。我们期望我们的研究能够确定 PLK4 在黑色素瘤中的确切作用及其作用对该肿瘤的诊断/预后以及治疗意义。