Role of polo like kinase 4 in melanomagenesis and melanoma progression

Polo 样激酶 4 在黑色素瘤发生和黑色素瘤进展中的作用

基本信息

批准号：
10421255
负责人：
Nihal Ahmad
金额：
--
依托单位：
WM S. MIDDLETON MEMORIAL VETERANS HOSP
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421255
关键词：
Afghanistan Apoptosis Archives BRAF gene Biology Biopsy Cancer Patient Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell Line Centrioles Centrosome Cessation of life Chemicals Cilia Climate Data Defect Dermatologic Development Diagnosis Diagnostic Diet Disease Disease Outcome Exposure to Female Gene Chips Genes Genetic Goals Growth Growth and Development function Healthcare Hospitals Human Human Resources In Vitro Incidence Iraq Laboratories Lead Literature Malignant Neoplasms Melanoma Cell Metastatic Melanoma Middle East Military Personnel Mission Modeling Molecular Mutation NOD/SCID mouse Neoplasms Nevus Nude Mice Outcome Study PLK1 gene Patients Phosphotransferases Play Process Protein-Serine-Threonine Kinases Proteins Proteomics RNA Interference Recurrence Research Resistance development Risk Role S-Phase Fraction Sampling Skin Skin Cancer Specimen Stress TP53 gene Testing Therapeutic Tissue Microarray Tissues Transgenic Mice Trimethoprim-Sulfamethoxazole UV Radiation Exposure United States Department of Veterans Affairs Validation Veterans War Work Xenograft procedure alpha Tubulin base cancer diagnosis cancer therapy cell transformation chemotherapy gastric cancer cell high risk human tissue improved in vitro Model in vivo indexing inhibitor knock-down liquid crystal polymer male melanocyte melanoma melanomagenesis military veteran mouse model neoplasm registry novel novel diagnostics novel strategies overexpression patient derived xenograft model pericentrin prognostic prospective response senescence small molecule small molecule inhibitor spectrograph standard of care suicidal targeted treatment therapy resistant tumor tumorigenic ultraviolet

项目摘要

SUMMARY: Melanoma is one of the most aggressive human cancers with approximately 87,110 new melanoma cases and 9,730 melanoma-related deaths predicted in the U.S. in 2017. Further, melanoma is a significant problem in Veterans. The US military currently is and has been engaged, in missions all over the world, including recently, in the Middle East (Iraq and Afghanistan). Many US military personnel, who are deployed to high ultraviolet (UV) index climates in tropical and subtropical zones are potentially at a higher risk for melanoma. Further, these personnel are not adequately protected because they possibly have survival priorities other than avoiding UV exposure. Based on the Veterans Affairs Central Cancer Registry (VACCR), melanoma is among the five most frequently diagnosed cancers among VA cancer patients. Unfortunately, the available therapeutic strategies have either failed to achieve >25% response or the responses are short-lived with developing resistance to therapy. Indeed, recent advances in the understanding of melanoma biology has led to the development of targeted therapies such as BRAF inhibitors (vemurafenib and dabrafenib) achieved improvement over chemotherapy for melanomas with BRAF-mutations. However, even with these new targeted approaches, most of the patients develop resistance, thereby failing to achieve lasting tumor regression. Therefore, further research is needed to understand the mechanism of melanoma development and progression. Polo-like kinase 4 (PLK4), a serine/threonine kinase, is the master regulator of centriole duplication. PLK4 is a low abundance suicidal kinase that is known to autophosphorylate itself to promote its own destruction to limit centriole duplication once per cell cycle. Based on recent research, PLK4 is emerging as a potential target for cancer treatment. PLK4 has been suggested to be involved in certain cancers. Interestingly, overexpression of PLK4 has been shown to result in supernumerary centrosomes and loss of primary cilia in transgenic mice and gastric cancer cells. Importantly, primary cilia exist in melanocytes and frequently lost in melanoma. Although limited information is available regarding the potential role of PLK4 in certain cancers, its involvement in melanoma development and progression has not been evaluated. In our preliminary data, we have found that PLK4 is overexpressed in melanoma cells and human tissues (in a limited number of specimens studied) and its inhibition via a small molecule inhibitor centrinone B results in a significant anti-proliferative response in multiple human melanoma cell lines. Thus, based on available literature and our preliminary data, we propose to test the hypothesis that PLK4 plays a critical role in melanoma development and progression and could serve as a novel target for melanoma management. The following specific aims are proposed; 1) to define the role of PLK4 in melanoma development and progression, employing a tissue microarray (TMA) created from retrospective melanoma tissues from Veteran patients, and an in vitro cell transformation model; 2) to determine the functional and mechanistic significance of PLK4 in melanoma (downstream mechanisms and effect on cilia formation), in vitro and in vivo; 3) to determine the therapeutic significance of PLK4 in melanoma in human-relevant mouse models of melanoma, namely, Braftm1Mmcm Ptentm1Hwu Tg(Tyr-cre/ERT2)13Bos/BosJ model and patient-derived xenografts (PDX) model. This may ultimately lead to development of novel diagnostic, prognostic or therapeutic approaches for melanoma. Since melanoma incidence seems to be higher in the Veteran population and our proposed study aimed at defining the molecular mechanism of melanoma development may lead to identification of novel strategies for the management of this deadly neoplasm. Therefore, our proposed work is relevant and significant to the health care of Veterans and is in line with the mission of the Department of Veteran Affairs.

概括：黑色素瘤是最具侵略性的人类癌症之一，大约87,110例新型黑色素瘤病例 2017年在美国预测的9,730例黑色素瘤死亡。此外，黑色素瘤是一个重要的问题在退伍军人中。美国军方目前已经并且已经从事世界各地的任务，包括最近，在中东（伊拉克和阿富汗）。许多部署到高处的美国军事人员热带和亚热带地区的紫外线（UV）指数气候可能面临黑色素瘤的风险更高。此外，这些人员没有得到充分保护避免紫外线暴露。根据退伍军人事务中央癌症登记处（VACCR），黑色素瘤是在VA癌症患者中，五个最常被诊断出的癌症。不幸的是，可用的治疗策略要么未能达到25％的反应，要么反应是短暂的，具有对治疗的抵抗力。确实，最新的理解发展黑色素瘤生物学的of导致了靶向疗法的发展，例如BRAF抑制剂（vemurafenib 和dabrafenib）对具有BRAF突变的黑色素瘤的化学疗法有所改善。然而，即使采用这些新的目标方法，大多数患者也会产生抗药性，从而无法实现持久的肿瘤回归。因此，需要进一步的研究来了解黑色素瘤的机制发展和发展。丝氨酸/苏氨酸激酶类似polo样激酶4（PLK4）是主调节剂中心重复。 PLK4是一种低丰度自杀激酶，已知可以自动磷酸化至促进其自身的破坏，以限制每个细胞周期一次的中心重复。根据最近的研究，PLK4是作为癌症治疗的潜在目标。建议PLK4参与某些癌症。有趣的是，PLK4的过表达已显示出可导致超生物中心体和转基因小鼠和胃癌细胞中原发性纤毛的丧失。重要的是，黑素细胞中存在原发性纤毛并且经常在黑色素瘤中迷失。尽管有限的有关PLK4潜在作用的信息有限在某些癌症中，尚未评估其参与黑色素瘤发育和进展。在我们的初步数据，我们发现PLK4在黑色素瘤细胞和人体组织中过表达（在有限的情况下研究的标本数量）及其通过小分子抑制剂中心酮B的抑制作用导致A 多种人黑色素瘤细胞系中的显着抗增殖反应。因此，基于可用的文献和我们的初步数据，我们建议检验PLK4在黑色素瘤的发育和进展，可以作为黑色素瘤管理的新目标。这提出了以下特定目标； 1）定义PLK4在黑色素瘤发育和进展中的作用，使用由退伍军人患者的回顾性黑色素瘤组织产生的组织微阵列（TMA），以及体外细胞转化模型； 2）确定PLK4在功能和机械意义上黑色素瘤（下游机制和对纤毛形成的影响），体外和体内； 3）确定 PLK4在黑色素瘤中黑色素瘤中的治疗意义，即黑色素瘤模型，即 BraftM1MMCM PTENTM1HWU TG（Tyr-CRE/ERT2）13BOS/BOSJ模型和患者衍生的异种移植物（PDX）模型。这最终可能导致黑色素瘤的新型诊断，预后或治疗方法的发展。由于在退伍军人人口中，黑色素瘤的发病率似乎较高，我们提出的研究针对定义黑色素瘤发育的分子机制可能导致确定新的策略这种致命的肿瘤的管理。因此，我们提出的工作与退伍军人的卫生保健，并符合退伍军人事务部的任务。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic Manipulation of Sirtuin 3 Causes Alterations of Key Metabolic Regulators in Melanoma.

DOI：
10.3389/fonc.2021.676077
发表时间：
2021
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Singh CK;George J;Chhabra G;Nihal M;Chang H;Ahmad N
通讯作者：
Ahmad N

Role of Polo-Like Kinase 4 (PLK4) in Epithelial Cancers and Recent Progress in its Small Molecule Targeting for Cancer Management.

DOI：
10.1158/1535-7163.mct-20-0741
发表时间：
2021-04
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Garvey DR;Chhabra G;Ndiaye MA;Ahmad N
通讯作者：
Ahmad N

CRISPR/Cas9-mediated Knockout of SIRT6 Imparts Remarkable Antiproliferative Response in Human Melanoma Cells in vitro and in vivo.

DOI：
10.1111/php.13305
发表时间：
2020-11
期刊：
Photochemistry and photobiology
影响因子：
3.3
作者：
Garcia-Peterson LM;Ndiaye MA;Chhabra G;Singh CK;Guzmán-Pérez G;Iczkowski KA;Ahmad N
通讯作者：
Ahmad N

Recent Advancements on Immunomodulatory Mechanisms of Resveratrol in Tumor Microenvironment.