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

推进针对 MYC 扩增的髓母细胞瘤的新治疗策略，这是儿童期最致命的脑肿瘤之一

• 批准号: 2601994
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2601994
• 关键词: Advancing; novel; treatment; strategies; MYC

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).

髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤。标准前期治疗（手术切除肿瘤、放疗和化疗）的进步使存活率达到约70%。我们的研究已经确定了四个共识分子亚组（MBWNT，Wnt/无翼激活; MBSHH，Sonic-hedgehog激活; MBGroup 3，Group 3;和MBGroup 4，Group 4），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，MBGroup 3（MBGroup 3-MYC）中的MYC癌基因扩增传达了令人沮丧的预后;患者通常在标准前期治疗后不久进展或复发，随后死于疾病（<10%生存率）。 因此，MBGroup 3-MYC占儿童癌症死亡的很高比例，是儿童癌症中最重要的未满足的临床挑战之一。该项目旨在使用综合疾病建模方法开发MBGroup 3-MYC的新疗法。迄今为止，我们已经开发了三个独立的同基因MBGroup 3细胞系模型（iMBGroup 3-MYC）与可调控的MYC表达，以研究MYC在耐药性中的作用。在这些细胞系模型中的高通量药物筛选已经确定了有前途的新MYC靶向药物，以供进一步研究。 该项目将推进这些早期发现，并将开发新的MBGroup 3-MYC小鼠模型，然后使用这些模型来测试新的MYC靶向药物并了解其作用机制。主要目标是：目标一：使用整合的化学信息学方法，优先考虑从iMBGroup 3-MYC细胞系模型的高通量筛选中鉴定出的MYC靶向药物。 目的二：建立新型MYC表达可调控的iMBGroup 3-MYC小鼠模型。目标三：使用患者来源的异种移植物建立新的MBGroup 3-MYC小鼠模型，以提供重新屈服于肿瘤内异质性的疾病相关模型，用于进一步评估所鉴定的MYC靶向药物。 目标四：在我们的新型MBGroup 3-MYC小鼠模型中测试和验证MYC靶向药物，包括疗效、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，该奖学金将提供;标准前期治疗难治性肿瘤的新治疗机会，以及MYC驱动的治疗难治性MBGroup 3替代前期策略的基本原理。重要的是，这些研究结果的翻译将通过儿童癌症和白血病小组，国际儿科肿瘤学会欧洲（SIOPE）和儿童癌症创新疗法（ITCC）等团体内的监督团队的既定网络和国际角色加速。