Polo-Like Kinase 1 as a Therapeutic Target in Medulloblastoma

描述（申请人提供）：髓母细胞瘤是儿童最常见的恶性脑肿瘤。尽管采用手术治疗，但这些高毒性治疗的放疗和化疗结果远未达到最佳效果。此外，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的预后非常差。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。通过整合基因组分析，我们最近发现Polo样激酶1 （PLK1）是髓母细胞瘤的潜在治疗靶点。PLK1对有丝分裂的调节至关重要，重要的是，抑制PLK1优先杀死癌细胞而不是正常细胞。然而，PLK1在成神经管细胞瘤发生中的功能作用尚不清楚。我们已经表明，抑制PLK1可抑制成神经管细胞瘤细胞的肿瘤细胞生长，并增加对电离辐射的敏感性。该提案的目的是提供PLK1抑制作为髓母细胞瘤治疗方法的临床前验证。核心假设是PLK1通过促进细胞适应Myc癌基因诱导的复制应激和促进电离辐射诱导的DNA损伤的修复来促进成髓细胞瘤细胞的存活。该建议的基本原理是，一旦PLK1作为成神经管细胞瘤的治疗靶点得到更好的理解，就可以开发新的联合治疗策略。为了解决这一假设，目标一的研究将通过检测Myc表达与PLK1抑制的合成致死相互作用，并比较PLK1在高Myc和低Myc的髓母细胞瘤中的抑制作用，来确定PLK1在髓母细胞瘤肿瘤发生中的作用。目的二是通过多种细胞系来源的异种移植物、患者来源的异种移植物和Myc驱动的髓母细胞瘤的新型遗传小鼠模型，在体内建立PLK1抑制剂BI6727和ON-013105的治疗效果和耐受性。目的三将验证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照成神经管细胞瘤细胞DNA损伤修复的工作假设。本研究将为早期临床研究提供科学依据和临床前数据，明确PLK1如何调控成神经管细胞瘤的发生，并确立PLK1作为成神经管细胞瘤的新治疗靶点。这些研究的完成有望通过产生结合PLK1抑制的新治疗策略来影响成神经管细胞瘤的治疗。

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.