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

microKinetic通过提供一种全新的方法来发现治疗生物标志物，从而掀起了多形性胶质母细胞瘤（GBM）治疗的革命。GBM是成人中最常见的原发性脑肿瘤，15年的中位生存期不变。肿瘤微环境是放化疗耐药的关键驱动因素。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，任何治疗不足的疾病仍然是单点失败。例如，放射治疗对组织氧合不可知，研究药物是根据脑渗透的二分标准选择的，而没有考虑通过异常血管系统产生的可变药代动力学（PK）。microKinetic将解决GBM理解中的4个关键空白。首先是：如何对肿瘤血管及其时间演化进行结构表型分析？作为回应，微动力将制定有史以来第一个方法，基于图论，适用于体内设置。其次，如何以足够的分辨率推断肿瘤组织的氧合和PK以改善治疗？利用我最近开发的计算方法，从生物物理的基本原理计算组织氧合和PK，微动力学将实现微米尺度的推理。第三，如何彻底校准和验证氧气和药物运输的计算预测？microKinetic将在结合结构和PK成像以及缺氧组织学的GBM临床前模型中验证预测。第四，我们缺乏临床可获得的肿瘤组织氧合和pk的预测指标。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测量）有可能成为个性化癌症治疗计划的变革性工具。

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.