Polo-Like Kinase 1 as a Therapeutic Target in Medulloblastoma

描述（由申请人提供）：髓母细胞瘤是最常见的类型的恶性脑肿瘤，折磨儿童。尽管采用手术、放疗和化疗进行治疗，但这些高毒性治疗的结果远非最佳。此外，有越来越多的证据表明，长期发病率，如神经认知缺陷和继发性肿瘤。特别是Myc高表达的髓母细胞瘤患者表现非常差。因此，迫切需要更有效的疗法来对抗这种疾病，特别是在高Myc表达的肿瘤中。利用整合基因组分析，我们最近确定波罗样激酶1（PLK 1）作为一个潜在的治疗靶点在髓母细胞瘤。PLK1对有丝分裂的调节至关重要，重要的是，PLK1的抑制优先杀死癌细胞而不是正常细胞。然而，PLK1在髓母细胞瘤肿瘤发生中的功能作用还不清楚。我们已经表明，PLK1的抑制导致肿瘤细胞生长的抑制和髓母细胞瘤细胞对电离辐射的敏感性增加。本提案的目的是提供PLK1抑制作为髓母细胞瘤治疗方法的临床前验证。中心假设是PLK1通过促进细胞对Myc癌基因诱导的复制应激的适应和促进电离辐射诱导的DNA损伤的修复来促进髓母细胞瘤细胞存活。这个建议的基本原理是，一旦PLK1作为一个治疗目标是更好地了解髓母细胞瘤，新的组合治疗策略可以开发。为了解决这一假设，目的一的研究将通过检查Myc表达与PLK1抑制的合成致死相互作用并比较高Myc与低Myc髓母细胞瘤中PLK1的抑制来确定PLK1在髓母细胞瘤肿瘤发生中的作用。目的二是使用多细胞系来源的异种移植物、患者来源的异种移植物和Myc驱动的成神经管细胞瘤的新型遗传小鼠模型来建立PLK1抑制剂BI 6727和ON-013105的体内治疗功效和耐受性。目的三是验证PLK1通过介导Rad 51的磷酸化和提高肿瘤起始细胞分数来促进辐射髓母细胞瘤细胞DNA损伤修复的工作假设。 拟议的研究将确定PLK1如何调节髓母细胞瘤肿瘤发生，并通过提供早期临床研究所需的科学依据和临床前数据，将PLK1确立为髓母细胞瘤的新治疗靶点。这些研究的完成预计会通过产生包含PLK1抑制的新型治疗策略来影响髓母细胞瘤治疗。

DESCRIPTION (provided by applicant): Medulloblastoma is the most common type of malignant brain tumor that afflicts children. Despite therapy with surgery, radiation and in chemotherapy outcomes of these highly toxic treatments are far from optimal. Further there is increasing evidence of long-term morbidity such as neurocognitive deficits and secondary tumors. In particular patients with high Myc expressing medulloblastoma do very poorly. Thus, there is a critical need for more effective therapies to combat this disease, particularly in the high Myc expressing tumors. Using integrated genomic analysis we have recently identified Polo like kinase 1 (PLK1) as a potential therapeutic target in medulloblastoma. PLK1 is critical for regulation of mitosis and importantly, inhibition of PLK1 preferentially kills cancer cells ove normal cells. However, the functional role of PLK1 in medulloblastoma tumorigenesis is not well understood. We have shown inhibition of PLK1 results in suppression of tumor cell growth and increased sensitivity to ionizing radiation in medulloblastoma cells. The objective of this proposal is to provide pre-clinical validation of PLK1 inhibition as a therapeutic approach in medulloblastoma. The central hypothesis is that PLK1 promotes medulloblastoma cell survival by fostering cell adaptation to Myc oncogene induced replicative stress and promoting repair of DNA damage induced by ionizing radiation. The rationale for this proposal is that once PLK1 as a therapeutic target is better understood in medulloblastoma, novel combination therapeutic strategies can be developed. To address the hypothesis the studies in aim one will determine the role of PLK1 in medulloblastoma tumorigenesis by examining the synthetic lethal interaction of Myc expression with PLK1 inhibition and comparing inhibition of PLK1 in high Myc versus low Myc medulloblastoma. Aim two is designed to establish the therapeutic efficacy and tolerability of PLK1 inhibitors BI6727 and ON-013105 in vivo using multiple cell line derived xenografts, patient derived xenografts and a novel genetic murine model of Myc driven medulloblastoma. Aim three will test the working hypothesis that PLK1 promotes DNA damage repair in irradiated medulloblastoma cells by mediating phosphorylation of Rad 51 and enhancing the tumor initiating cell fraction. The proposed studies will define how PLK1 regulates medulloblastoma tumorigenesis and establish PLK1 as a novel therapeutic target in medulloblastoma by providing the scientific rationale and preclinical data required for early phase clinical studies. Completion of these studies is expected impact medulloblastoma therapy by resulting in novel therapeutic strategies incorporating PLK1 inhibition.