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.

项目摘要 结直肠癌（CRC）是全球第三大流行癌症，每年导致超过85万人死亡， 其中5万人在美国。只有少数小分子药物被批准用于患者治疗。小 分子药物通常易于配制，并且比基于抗体的药物对患者更方便， 联合治疗已被证明是非常有效的- FOLFOX（亚叶酸，5 FU和奥沙利铂）是主要的 例如CRC。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种肿瘤细胞的作用。 代表乳腺、结肠和胰腺的线条，并指出“整体协同作用是罕见的......”我们想知道， 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， 肿瘤细胞在组织培养塑料上单层培养， 在复杂基质存在下的三维培养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，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，我们建议使用我们的良好表征的人类细胞为基础的血管化微肿瘤（VMT）模型 为了测试多种药物组合对结肠癌细胞（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，或者可以靶向在单一培养中不存在的肿瘤-基质相互作用。我确 我已经确定了一种药物，只在VMT中阻断肿瘤生长，而不是在单层培养中或在体外培养中。 球状体VMT平台包括体外灌注的活毛细血管床，其向血管供应营养物。 和体内的情况一样。微小肿瘤，由肿瘤细胞和间质组成 包埋在细胞外基质（ECM）中的细胞在组织室中生长，这些细胞被包围， 被微血管穿透，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方法，在肿瘤生物学中，血管和基质成分的重塑是 肿瘤进展。 我们的假设是：VMT平台可以揭示简单2D中看不到的积极药物相互作用， 单一栽培为了检验这一假设，我们将挑战五个肿瘤系，代表5个CRIS类别， 结肠癌，对25种药物，代表了大多数主要的信号通路，在所有成对组合。 然后，我们将用5个患者来源的肿瘤系重复该研究。我们的目标是：1。确定剂量反应 VMT中每种药物的曲线。2.在VMT中测试所有药物的双向组合。3.比较药物 VMT中肿瘤细胞系与患者来源肿瘤的反应。