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治疗 效果不如预期，主要是因为内在和/或相对较快地获得了耐药性。 细胞异质性，特别是肿瘤/间质成分的异质性和表达的变化 膜结合受体，已被认为是抗癌的重要驱动因素 治疗。然而，到目前为止，还没有分析工具可以提供在体外复制这些异质性的方法。 并且可以定量地监测治疗性抗体或药物抗体结合物与其 各自的靶点，这对药物传递的效果至关重要。在这里，我们建议整合一种生物制造 首次利用3D光学分子成像平台研究对肿瘤细胞的影响 异质性，即成分异质性以及受体水平表达异质性(即， HER2+、EGFR和TFN)对靶-受体结合的影响。我们方法的独特特点是 能够按需制造“组织学级”3D异种乳腺肿瘤系统并进行量化 这些系统中的配体-受体结合超出了目前显微镜的深度限制。为了实现我们的目标 为了实现我们的目标，我们组建了一支拥有成熟专业知识和合作轨迹的多学科研究团队 录制节目的方方面面。在这个项目完成后，我们将整合这个分析 评估知名药物载体在异质3D癌症系统中的受体接合的平台。 该平台有望通过提供以下工具和方法来推进个性化医疗 用于批判性地评估量身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.