Role of tumor heterogeneity on receptor engagement

肿瘤细胞异质性对受体结合MPI的影响：Barroso，Corr和Intes 摘要 肿瘤学中的精准医学在改善患者预后和福祉方面显示出巨大的前景。 然而，目前作用于与癌症相关的特定分子靶点的临床靶向疗法具有以下缺点： 效果不如预期，主要是由于内在的和/或相对快速的耐药性。 细胞异质性，特别是肿瘤/间质组成异质性和表达变异 膜结合受体，已被牵连作为一个重要的驱动力的耐药性抗癌 治疗。虽然，迄今为止，没有分析工具可以提供在体外复制这些异质性的方法 并且可以定量监测治疗性抗体或药物-抗体缀合物与它们的结合， 这对药物递送功效至关重要。在此，我们建议将生物制造 该平台具有3D光学分子成像，首次研究了肿瘤细胞的影响， 异质性，即组成异质性以及受体水平表达异质性（即， Her 2+、EGFR和Tfn）对靶受体结合的影响。我们方法的独特之处在于 能够按需制造“组织学级”3D异质性乳腺肿瘤系统， 这些系统中的配体-受体参与超出了目前显微镜的深度限制。实现我们 目标，我们已经组建了一个多学科的研究团队，具有既定的专业知识和合作轨道 在节目的各个方面都有记录。在这个项目完成后，我们将整合这个分析 该平台用于评估已知药物载体在异质性3D癌症系统中的受体接合。 该平台预计将通过提供可以实现的工具和方法来推进个性化医疗。 用于严格评估定制的治疗管理策略。

Effect of tumor cell heterogeneity on receptor engagement MPIs: Barroso, Corr and Intes ABSTRACT Precision medicine in oncology has shown great promise in improving patient prognosis and well-being. However, current clinical targeted therapies that act on specific molecular targets associated with cancer have been less effective than anticipated, mainly due to intrinsic and/or relatively rapid acquisition of resistance. Cellular heterogeneity, in particular tumor/stroma compositional heterogeneity and variations in the expression of membrane-bound receptors, has been implicated as an important driver of resistance to anti-cancer treatments. Though, to date, no analytical tool can provide means to replicate these heterogeneities in vitro and can monitor quantitatively the binding of therapeutic antibodies or drug-antibody conjugates to their respective targets, which is critical for drug deliver efficacy. Herein, we propose to integrate a biomanufacturing platform with 3D optical molecular imaging to investigate, for the first time, the influence of tumor cell heterogeneity, namely compositional heterogeneity as well as receptor level expression heterogeneity (i.e., Her2+, EGFR and Tfn), on target-receptor engagement. The unique characteristics of our approach are the ability to manufacture on demand “histology grade” 3D heterogeneous breast tumor systems and quantify ligand-receptor engagement in these systems beyond the current depth limits of microscopy. To achieve our goals, we have assembled a multidisciplinary research team with established expertise and collaboration track record in all facets on the program. Upon completion of this project, we will have integrated this analytical platform to assess receptor engagement of well-known drug carriers in heterogeneous 3D cancer systems. This platform is expected to advance personalized medicine by providing tools and approaches that can be used to critically assess tailored therapy management strategies.