microKinetic: Predicting oxygen and drug kinetics at the micrometre scale in glioblastoma

microKinetic：预测胶质母细胞瘤微米级的氧和药物动力学

• 批准号: EP/X025705/1
• 负责人: Miguel Bernabeu Llinares
• 金额: $ 219.62万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX025705%2F1
• 关键词: microKinetic; Predicting; oxygen; drug; kinetics

microKinetic sets off to revolutionise the treatment of glioblastoma multiforme (GBM) by delivering a radically new approach to the discovery of treatment biomarkers. GBM is the commonest primary brain tumour in adults, with a dismal median survival unchanged over 15 years. Tumour microenvironment is a key driver of chemoradioresistance. However, there are no spatially resolved microenvironmental biomarkers associated with prognosis and treatment response prediction, and any undertreated disease remains the single point of failure. For example, radiotherapy is delivered agnostic to tissue oxygenation, and investigational drugs are selected on dichotomous criteria for brain penetration, without considering variable pharmacokinetics (PK) via aberrant vasculature. microKinetic will address 4 key gaps in GBM understanding. The first is: how to structurally phenotype tumour vasculature and its temporal evolution? In response, microKinetic will formulate the first-ever method, based on Graph Theory, suitable for in vivo settings. Secondly, how to infer tumour tissue oxygenation and PK at sufficient resolution to improve treatment? Leveraging computational methods recently developed by me to calculate tissue oxygenation and PK from biophysical first principles, microKinetic will enable inference at the micrometre scale. Thirdly, how to thoroughly calibrate and validate computational predictions of oxygen and drug transport? microKinetic will validate predictions in a preclinical model of GBM combining structural and PK imaging, and hypoxia histology. Fourthly, we lack clinically accessible predictors of tumour tissue oxygenation and PK. microKinetic will be in position to investigate, for the first time, spatial correlations between coarse-grain vascular structure, tissue oxygenation and drug penetration. Such structural biomarkers (measurable in patients through biopsy or next-generation imaging) have the potential to become a transformative tool for personalised cancer treatment planning.

microKinetic通过提供一种全新的方法来发现治疗生物标志物，从而彻底改变多形性胶质母细胞瘤（GBM）的治疗。GBM是成人中最常见的原发性脑肿瘤，15年以上的中位生存率没有变化。肿瘤微环境是化学放射抗性的关键驱动因素。然而，没有与预后和治疗反应预测相关的空间分辨微环境生物标志物，并且任何治疗不足的疾病仍然是单点失败。例如，放射治疗与组织氧合无关，并且根据脑渗透的二分法标准选择研究药物，而不考虑通过异常血管系统的可变药代动力学（PK）。microKinetic将解决GBM理解中的4个关键差距。第一个问题是：如何在结构上表现肿瘤血管及其时间演变？作为回应，microKinetic将制定第一个基于图论的方法，适用于体内环境。其次，如何以足够的分辨率推断肿瘤组织氧合和PK以改善治疗？利用我最近开发的计算方法，从生物物理学第一原理计算组织氧合和PK，microKinetic将实现微米级的推断。第三，如何彻底校准和验证氧气和药物运输的计算预测？microKinetic将在GBM的临床前模型中验证预测，该模型结合了结构和PK成像以及缺氧组织学。第四，我们缺乏肿瘤组织氧合和PK的临床可获得的预测因子。microKinetic将首次研究粗颗粒血管结构、组织氧合和药物渗透之间的空间相关性。这种结构生物标志物（通过活检或下一代成像在患者中可测量）有可能成为个性化癌症治疗计划的变革性工具。