In search of synergistic drug interactions in cancer

寻找癌症中的协同药物相互作用

• 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
• 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

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.

项目总结 结直肠癌(CRC)是全球第三大最常见的癌症，每年导致超过85万人死亡， 在美国，有5万个这样的人。只有少数小分子药物被批准用于患者治疗。小的 分子药物往往比基于抗体的药物更容易配制，对患者更方便，而且 事实证明，联合治疗非常有效-FOLFOX(亚叶酸、5FU和奥沙利铂)是首选方案 CRC中的示例。最近的一项研究评估了2,025种临床相关的两种药物组合对125个肿瘤细胞的作用 代表乳房、结肠和胰腺的线条，并指出“总体来说，协同作用是罕见的…”我们想知道是否 这种药物-药物相互作用的缺乏可能是简单的和非生理学的环境的产物，在这种环境中 肿瘤细胞的生长--在组织培养塑料上进行单层培养--以及是否有更具生理性的环境 在存在复杂基质的情况下进行三维培养可能会产生不同的结果。我们的导游 因此，这项研究的假设是，一个更复杂的、更具生理学的人类肿瘤模型将揭示 潜在的临床相关药物协同效应。 在这项研究中，我们建议使用我们的基于人类细胞的血管微肿瘤(VMT)模型 为了测试多种药物组合对结肠癌细胞(系和患者来源的)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2D培养中，或者可能针对单一培养中不存在的肿瘤-间质相互作用。事实上，我们 已经确定了一种仅在VMT中阻止肿瘤生长的药物，而不是在单层培养中或在 椭球体。VMT平台包括体外灌流的活毛细血管床，为 周围组织的方式与他们在体内所做的大致相同。微肿瘤，由肿瘤细胞和间质组成 嵌入细胞外基质(ECM)中的细胞在组织腔中生长，这些细胞被包围并 被支持其生长的微血管穿透。这是一个灵活而强大的平台，也是 这是研究肿瘤生物学的理想选择，在肿瘤生物学中，血管和间质成分的重塑是关键 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， 单一培养。为了验证这一假设，我们将挑战五个肿瘤株，代表五个CRI类别 结肠癌，对25种药物，代表了所有配对组合中的大多数主要信号通路。 然后，我们将对5个患者来源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.在VMT中测试所有双向药物组合。3.比较药物 VMT中肿瘤系与患者来源肿瘤的反应。