Advancing novel treatment strategies for MYC-amplified medulloblastoma, one of the most fatal brain tumours of childhood

髓母细胞瘤(MB)是儿童最常见的恶性脑肿瘤。标准前期治疗(手术切除肿瘤、放射治疗和化疗)的进展已使存活率达到约70%。我们的研究确定了四个共识的分子亚群(MBWNT，Wnt/Wingless激活；MBSHH，Sonic-Hedgehog激活；MBGroup3，Group3；和MBGroup4，Group4)，具有不同的第二代亚型、基因组特征和临床相关性。重要的是，MBGroup3(MBGroup3-MYC)中的MYC癌基因扩增表明预后很差；患者通常进展，或在标准的前期治疗后不久复发，随后死于疾病(&lt；10%的存活率)。因此，MBGroup3-MYC在儿童癌症死亡中占很高比例，是儿童癌症中最重要的未满足的临床挑战之一。该项目旨在利用全面的疾病建模方法为MBGroup3-MYC开发新的治疗方法。到目前为止，我们已经建立了三个独立的可调节MYC表达的等基因MBGroup3细胞系模型(iMBGroup3-MYC)来研究MYC在耐药中的作用。在这些细胞系模型中的高通量药物筛选已经发现了有希望的新的MYC靶向药物用于进一步研究。该项目将推进这些早期发现，并将开发新的MBGroup3-MYC小鼠模型，然后使用这些模型测试新的MYC靶向药物并了解它们的作用机制(S)。主要目标是：目标一：在我们的iMBGroup3-MYC细胞系模型中，使用集成的化学信息学方法优先考虑从高通量筛选中识别的MYC靶向药物。目的：建立可调控MYC基因表达的新型iMBGroup3-MYC小鼠模型。目的：利用患者来源的异种移植建立新的MBGroup3-MYC小鼠模型，为进一步评价MYC靶向药物提供疾病相关模型。目的：在我们的新型MBGroup3-MYC小鼠模型上测试和验证MYC靶向药物，包括药效、药代动力学和药效学研究，以确定进入未来临床试验的最佳药物。总之，这项研究将为对标准前期治疗无效的肿瘤提供新的治疗机会，以及在MYC驱动的治疗中替代前期治疗策略--难治性MBGroup3的基本原理。重要的是，将通过监督小组在儿童癌症和白血病小组、欧洲国际儿科肿瘤学会(SIOPE)和癌症儿童创新疗法(ITCC)等组织内建立的网络和监督小组的国际作用，加快这些结果的翻译。

Medulloblastoma (MB) is the commonest malignant childhood brain tumour. Advances in standard upfront-treatments (surgical removal of tumour, radiotherapy and chemotherapy) have led to survival rates of approximately 70%. Our research has identified four consensus molecular subgroups (MBWNT, Wnt/wingless-activated; MBSHH, Sonic-hedgehog-activated; MBGroup3, Group3; and MBGroup4, Group4), with divergent second-generation subtypes, genomic characteristics, and clinical relevance. Importantly, MYC oncogene amplification in MBGroup3 (MBGroup3-MYC) conveys a dismal prognosis; patients typically progress, or relapse shortly after standard upfront-treatment and subsequently die of disease (<10% survival). MBGroup3-MYC thus accounts for a high proportion of childhood cancer deaths, and is one of the most significant unmet clinical challenges in childhood cancer. This project aims to develop new therapies for MBGroup3-MYC using comprehensive disease modelling approaches. To date, we have developed three independent isogenic MBGroup3 cell-line models (iMBGroup3-MYC) with regulable MYC expression to investigate the role of MYC in drug resistance. High-throughput drug screening in these cell-line models has already identified promising new MYC-targeting drugs for further investigation. This project will advance these early findings and will develop novel MBGroup3-MYC mouse models, then use these to test new MYC-targeting drugs and understand their mechanism(s) of action. The major objectives are: Objective I: To use integrated chemo-informatics approaches to prioritise MYC-targeting drugs identified from high-throughput screens in our iMBGroup3-MYC cell-line models. Objective II: To develop and characterise novel iMBGroup3-MYC mouse models with regulable MYC expression. Objective III: To establish new MBGroup3-MYC mouse models using patient-derived xenografts, to provide disease-relevant models which re-capitulate intra-tumoural heterogeneity, for further assessment of MYC-targeting drugs identified. Objective IV: To test and validate MYC-targeting drugs in our novel MBGroup3-MYC mouse models, including, efficacy, pharmacokinetic and pharmacodynamic studies, to identify best agents to advance into future clinical trials. In summary, this studentship will provide; new therapeutic opportunities in tumours refractory to standard upfront-treatment and the rationale for alternative upfront-strategies in MYC-driven treatment-refractory MBGroup3. Importantly, translation of these findings will be expedited through established networks and international roles of the supervisory team within groups such as the Children's Cancer and Leukaemia Group, the International Society of Paediatric Oncology Europe (SIOPE), and Innovative Therapies for Children with Cancer (ITCC).