Polo-Like Kinase 1 as a Therapeutic Target in Medulloblastoma

描述(申请人提供)：髓母细胞瘤是最常见的恶性脑肿瘤类型，困扰儿童。尽管可以通过手术、放疗和化疗来治疗，但这些高毒性治疗的结果远非最佳。此外，越来越多的证据表明有长期的发病率，如神经认知缺陷和继发性肿瘤。特别是，髓母细胞瘤高Myc表达的患者表现非常差。因此，迫切需要更有效的治疗方法来对抗这种疾病，特别是在Myc高表达的肿瘤中。通过综合基因组分析，我们最近发现Polo-like kinase1(PLK1)是髓母细胞瘤的潜在治疗靶点。PLK1对有丝分裂的调控至关重要，重要的是，抑制PLK1优先杀死癌细胞而不是正常细胞。然而，PLK1在髓母细胞瘤发生中的作用还不是很清楚。我们发现PLK1的抑制可以抑制髓母细胞瘤细胞的生长，并增加其对电离辐射的敏感性。这项建议的目的是提供PLK1抑制作为髓母细胞瘤治疗方法的临床前验证。核心假设是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引起的DNA损伤的修复来促进髓母细胞瘤细胞的存活。这一建议的基本原理是，一旦PLK1作为治疗靶点在髓母细胞瘤中得到更好的理解，就可以开发新的联合治疗策略。为了解决这一假说，Aim中的研究一将通过检测Myc表达和PLK1抑制的合成致死性相互作用，并比较高Myc和低Myc髓母细胞瘤中PLK1的抑制，来确定PLK1在髓母细胞瘤发生中的作用。目的研究PLK1抑制剂BI6727和On-013105在多细胞系异种移植、患者来源异种移植和一种新的小鼠髓母细胞瘤遗传模型中的治疗效果和耐受性。目的验证PLK1通过介导Rad 51的磷酸化和增加肿瘤起始细胞比例来促进受照射的髓母细胞瘤细胞DNA损伤修复的假设。拟议的研究将确定PLK1如何调控髓母细胞瘤的发生，并通过提供早期临床研究所需的科学理论和临床前数据，确立PLK1作为髓母细胞瘤的新治疗靶点。这些研究的完成有望通过引入PLK1抑制的新治疗策略来影响髓母细胞瘤的治疗。

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.