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

MicroKinetic将通过提供一种发现治疗生物标记物的全新方法，为多形性胶质母细胞瘤(GBM)的治疗带来革命性的变化。基底节细胞瘤是成人最常见的原发脑瘤，15年来的中位生存期没有变化。肿瘤微环境是化疗-放射耐药的关键驱动因素。然而，没有空间分辨的微环境生物标记物与预后和治疗反应预测相关，任何未得到充分治疗的疾病仍然是单一的失败点。例如，放射治疗与组织氧合无关，研究药物的选择基于脑穿透的二分法标准，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：肿瘤血管的结构表型及其时间演变？作为回应，MicroKinetic将基于图论制定出第一种适用于活体环境的方法。其次，如何在足够的分辨率下推断肿瘤组织的氧合和PK，以提高治疗水平？利用我最近开发的计算方法，从生物物理第一原理计算组织氧合和PK，MicroKinetic将能够在微米尺度上进行推断。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，我们缺乏临床可用的肿瘤组织氧合和PK的预测指标。MicroDynamtic将首次研究粗粒血管结构、组织氧合和药物渗透之间的空间相关性。这种结构生物标记物(可通过活组织检查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.