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

• 批准号: 10046297
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046297
• 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/antagonist; 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

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： 黑色素瘤是最具侵袭性的人类癌症之一，约有 87,110 例新黑色素瘤病例 预计 2017 年美国将有 9,730 例与黑色素瘤相关的死亡。此外，黑色素瘤是一个严重的问题 在退伍军人中。美国军队目前正在并且一直在世界各地执行任务，包括 最近，在中东（伊拉克和阿富汗）。许多部署在高层的美军人员 热带和亚热带地区的紫外线 (UV) 指数气候可能面临更高的黑色素瘤风险。 此外，这些人员没有得到充分的保护，因为他们可能有除 避免紫外线照射。根据退伍军人事务中心癌症登记处 (VACCR)，黑色素瘤属于 VA 癌症患者中最常诊断出的五种癌症。 不幸的是，现有的治疗策略要么未能达到 >25% 的缓解率，要么 反应是短暂的，并且会对治疗产生耐药性。事实上，最近在理解上取得了进展 黑色素瘤生物学的发展导致了靶向治疗的发展，例如 BRAF 抑制剂（维莫非尼） 和达拉非尼（dabrafenib））在治疗具有 BRAF 突变的黑色素瘤方面取得了优于化疗的效果。然而， 即使采用这些新的有针对性的方法，大多数患者也会产生耐药性，从而无法实现 肿瘤持久消退。因此，需要进一步研究来了解黑色素瘤的机制 发展和进步。 Polo 样激酶 4 (PLK4) 是一种丝氨酸/苏氨酸激酶，是 中心粒重复。 PLK4 是一种低丰度自杀激酶，已知其自身磷酸化 促进其自身破坏，以限制每个细胞周期的中心粒复制一次。根据最近的研究，PLK4 是 正在成为癌症治疗的潜在靶点。 PLK4 已被建议参与某些 癌症。有趣的是，PLK4 的过度表达已被证明会导致多余的中心体和 转基因小鼠和胃癌细胞中初级纤毛的丧失。重要的是，初级纤毛存在于黑素细胞中 并且经常在黑色素瘤中丢失。尽管有关 PLK4 潜在作用的信息有限 在某些癌症中，其与黑色素瘤发生和进展的关系尚未得到评估。在我们的 初步数据显示，我们发现PLK4在黑色素瘤细胞和人体组织中过度表达（在有限的情况下） 研究的样本数量）及其通过小分子抑制剂 centrinone B 的抑制导致 在多种人类黑色素瘤细胞系中具有显着的抗增殖反应。因此，根据现有的 根据文献和我们的初步数据，我们建议检验 PLK4 在 黑色素瘤的发生和进展可以作为黑色素瘤治疗的新靶点。这 提出了以下具体目标； 1) 定义 PLK4 在黑色素瘤发生和进展中的作用， 采用由退伍军人患者的回顾性黑色素瘤组织创建的组织微阵列（TMA），以及 体外细胞转化模型； 2) 确定PLK4在中的功能和机制意义 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 在人类相关黑色素瘤小鼠模型中对黑色素瘤的治疗意义，即 Braftm1Mmcm Ptentm1Hwu Tg(Tyr-cre/ERT2)13Bos/BosJ 模型和患者来源的异种移植物 (PDX) 模型。这 可能最终导致黑色素瘤新诊断、预后或治疗方法的发展。 由于退伍军人群体中黑色素瘤的发病率似乎更高，因此我们提出的研究旨在 确定黑色素瘤发展的分子机制可能会导致确定新的治疗策略 这种致命肿瘤的治疗。因此，我们提出的工作对于 退伍军人的医疗保健，符合退伍军人事务部的使命。