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.

项目概要结直肠癌 (CRC) 是全球第三大常见癌症，每年导致超过 850,000 人死亡，在美国，只有少数小分子药物被批准用于患者治疗。分子药物通常比抗体药物更容易配制并且对患者来说更方便，并且联合疗法已被证明相当有效——FOLFOX（亚叶酸、5FU 和奥沙利铂）是主要药物最近的一项研究评估了 CRC 中 125 个肿瘤细胞的 2,025 种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“总体上的协同作用是罕见的……”我们想知道是否这种药物间相互作用的缺乏可能是简单和非生理环境的产物，在这种环境中，这些药物肿瘤细胞的生长——组织培养塑料上的单层培养——以及是否有更生理的环境在复杂基质存在的情况下进行 3 维培养可能会产生不同的结果。因此，这项研究的假设是，一个更复杂的人类肿瘤生理模型将揭示潜在的临床相关药物协同作用。在这项研究中，我们建议使用我们基于人类细胞的血管化微肿瘤（VMT）模型测试多种药物组合对结肠癌细胞（细胞系和患者来源）的潜在协同作用，探索药物可能针对不一定活跃的途径和途径组合的想法在二维培养物中，或者可能针对单一培养物中不存在的肿瘤-基质相互作用。已经鉴定出一种药物只能在 VMT 中阻止肿瘤生长，而不能在单层培养物或细胞中阻止肿瘤生长。 VMT 平台包括体外灌注活毛细血管床，为细胞提供营养。周围组织的形成方式与体内微肿瘤非常相似，由肿瘤细胞和基质组成。嵌入细胞外基质 (ECM) 的细胞在组织室中生长，这些细胞被包围并被微血管渗透，支持它们的生长，这是一个灵活而强大的平台。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研究肿瘤生物学的关键肿瘤进展。我们的假设是：VMT 平台可以揭示简单 2D 中未见的积极药物相互作用，为了检验这一假设，我们将挑战五个肿瘤系，代表 5 个 CRIS 类别。结肠癌，针对 25 种药物，代表大多数主要信号传导途径，在所有配对组合中。然后，我们将用 5 个患者来源的肿瘤细胞系重复这项研究，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 中肿瘤系的反应与患者来源的肿瘤的反应。