In search of synergistic drug interactions in cancer

寻找癌症中的协同药物相互作用

基本信息

批准号：
10651215
负责人：
CHRISTOPHER C. W. HUGHES
金额：
$ 20.57万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651215
关键词：
3-Dimensional Adherent Culture Adopted Antibodies Antineoplastic Agents Biological Assay Blood Vessels Breast Cancer Model Categories Cell Line Cells Cetuximab Colon Colon Carcinoma Colorectal Cancer Combined Modality Therapy Complex Cultured Tumor Cells Data Data Set Dose Drug Combinations Drug Interactions Drug Screening Drug Synergism Extracellular Matrix Fibroblasts Fluorouracil Gene Expression Profile Goals Grant Growth Human In Vitro Leucovorin Malignant Neoplasms Modeling Mus Nutrient Pancreas Pathway interactions Patients Penetration Perfusion Persons Pharmaceutical Preparations Pharmacotherapy Physiological Process Signal Pathway Stromal Cells Testing Tissues Tumor Biology Tumor Cell Line Vascular remodeling Vascularization analysis pipeline bevacizumab cancer cell capillary bed clinical predictors clinically relevant combinatorial design flexibility human model in vivo irinotecan monolayer neoplastic cell novel anticancer drug novel drug combination oxaliplatin panitumumab physiologic model response scale up small molecule sound success synergism tissue culture tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY Colorectal cancer (CRC) is the third most prevalent cancer worldwide, killing over 850,000 people every year, 50,000 of these in the US. Only a handful of small molecule drugs are approved for patient treatment. Small molecule drugs are often easy to formulate and more convenient for patients than antibody-based drugs, and combination therapies have proved quite effective – FOLFOX (folinic acid, 5FU and oxaliplatin) being the prime example in CRC. A recent study evaluated 2,025 clinically-relevant two-drug combinations on 125 tumor cell lines representing breast, colon and pancreas and noted that “synergy overall was rare…” We wondered whether this lack of drug-drug interaction might be a product of the simple and non-physiologic setting in which these tumor cells were grown – monolayer cultures on tissue culture plastic – and whether a more physiologic setting of 3-dimensional culture in the presence of a complex stroma might yield a different result. Our guiding hypothesis for this study, therefore, is that a more complex and physiological model of human tumors will reveal potentially clinically-relevant drug synergies. In this study we propose to use our well-characterized human cell-based Vascularized Micro-Tumor (VMT) model to test multiple drug combinations for potential synergies on colon cancer cells (both lines and patient-derived), exploring the idea that drugs may target pathways and combinations of pathways that are not necessarily active in 2D cultures, or may target tumor-stroma interactions that are just not present in monocultures. Indeed, we have already identified a drug that blocks tumor growth only in the VMT, and not in monolayer culture or in spheroids. The VMT platform comprises perfused living capillary beds in vitro that supply nutrients to the surrounding tissue in much the same way they do in vivo. Microtumors, comprised of tumor cells and stromal cells, embedded in extracellular matrix (ECM) are grown in the tissue chambers and these are surrounded and penetrated by the micro-vessels, which support their growth. This is a flexible and powerful platform, and one that is ideal for studying tumor biology, where remodeling of the vascular and stromal components is key to tumor progression. Our hypothesis is that: the VMT platform can reveal positive drug interactions not seen in simple 2D, monocultures. To test this hypothesis we will challenge five tumor lines, representing the 5 CRIS categories of colon cancer, against 25 drugs, representing most of the major signaling pathways, in all pairwise combinations. We will then repeat this study with 5 patient-derived tumor lines. Our Aims are: 1. Establish dose-response curves for each drug in the VMT. 2. Test all 2-way combinations of drugs in the VMT. 3. Compare drug responses in tumor lines versus patient-derived tumors in the VMT.

项目摘要大肠癌（CRC）是全球第三大流行的癌症，每年造成超过850,000人，其中50,000个在美国。仅批准少数小分子药物进行患者治疗。小的与基于抗体的药物相比，分子药物通常易于制造，并且对于患者而言更方便，并且事实证明，联合疗法非常有效-FOLFOX（叶酸，5FU和Oxaliplatin）是素数 CRC中的示例。最近的一项研究评估了125个肿瘤细胞上的2,025个临床上与临床相关的两种药物组合代表乳房，结肠和胰腺的线条，并指出“整体协同作用很少……”我们想知道是否想知道缺乏药物互动可能是简单和非生理环境的产物，在这些环境中种植肿瘤细胞 - 组织培养塑料上的单层培养物，以及更生理的环境在复杂基质存在下的3维培养物可能会产生不同的结果。我们的指导因此，这项研究的假设是，人类肿瘤的更复杂和物理模型将揭示潜在的与临床相关的药物协同作用。在这项研究中，我们建议使用我们特征良好的人类细胞基于血管化的微肿瘤（VMT）模型为了测试多种药物组合的结肠癌细胞（线和患者衍生）的潜在协同作用，探索药物可能靶向不一定活跃的途径的途径和组合的想法在2D培养物中，或者可能靶向仅在单一培养物中不存在的肿瘤相互作用。确实，我们已经确定了一种仅在VMT中阻断肿瘤生长的药物，而不是单层培养物或在球体。 VMT平台由体外灌注的生活毛细血管床组成，可为营养提供营养周围的组织以与体内的方式相同。由肿瘤细胞和基质组成的微肿块嵌入细胞外基质（ECM）中的细胞在组织室中生长，它们周围是周围的，并且由微船长穿透，支持其生长。这是一个灵活而强大的平台，一个这是研究肿瘤生物学的理想选择，其中血管和基质成分的重塑是至关重要的肿瘤进展。我们的假设是：VMT平台可以揭示在简单2D中看不到的阳性药物相互作用，单一培养。为了检验这一假设，我们将挑战五个肿瘤线，代表5个CRIS类别在所有成对组合中，针对25种药物，代表大多数主要信号通路。然后，我们将使用5个患者衍生的肿瘤系重复这项研究。我们的目标是：1。建立剂量反应 VMT中每种药物的曲线。 2。测试VMT中药物的所有2路组合。 3。比较药物 VMT中肿瘤线与患者衍生的肿瘤的反应。