Modeling Therapy of Disseminated Cancer Cells in Bone Marrow (PQ 17)

骨髓中播散性癌细胞的建模治疗 (PQ 17)

基本信息

批准号：
8532861
负责人：
Gary D Luker
金额：
$ 34.09万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532861
关键词：
Adjuvant Antineoplastic Agents Bone Marrow Bone Marrow Cells Breast Cancer Cell Cancer cell line Cell Culture System Cell Culture Techniques Cell Line Cells Cessation of life Characteristics Clinical Communities Data Development Diagnosis Disease Drug Kinetics Drug Targeting Drug resistance Drug usage Endothelium Frequencies Heterogeneity Human Human Cell Line Hypoxia Image Analysis Imaging Techniques In Vitro Lead Lung Malignant Neoplasms Mammary Neoplasms Measures Mesenchymal Stem Cells Methods Modeling Molecular Monitor Mus Neoplasm Metastasis New Agents Osteoblasts Outcome Oxygen measurement, partial pressure, arterial Patients Pharmaceutical Preparations Physiological Physiology Postoperative Period Primary Neoplasm Proliferating Prostate Recurrence Recurrent Malignant Neoplasm Recurrent disease Relapse Relative (related person)Reporter Research Risk Sampling Signal Pathway Signal Transduction Site Solid Specimen Stromal Cells System Technology Testing Time Translations Treatment Protocols Tumor Subtype Xenograft procedure anticancer research cancer cell cancer therapy cancer type cell type chemotherapy cost cytokine cytotoxicity drug development drug efficacy drug testing imaging modality improved in vivo innovation malignant breast neoplasm molecular imaging mortality mouse model neoplastic cell optical imaging outcome forecast prevent response self-renewal tumor

项目摘要

DESCRIPTION (provided by applicant): As determined by the cancer research community and NCI, inefficiencies and inaccuracies of existing methods for drug testing are critical obstacles preventing development and clinical translation of new drugs to dramatically improve cancer therapy (Provocative Question 17). To overcome these obstacles, we will develop a new 3D cell culture model of disseminated breast cancer cells in the bone marrow microenvironment. Our focus on the bone marrow microenvironment is driven by the high frequency of disseminated cancer cells even in patients with seemingly localized primary tumors, limited activity of drugs against metastases relative to primary tumors, and > 90% of cancer mortality caused by metastatic disease. Our model will incorporate multiple types of human bone marrow stromal cells, including mesenchymal stem cells, endothelium, and osteoblasts. One or more of these cell types form protective niches that may confer drug resistance to metastatic breast cancer cells through intercellular signaling pathways. We will optimize culture conditions to reproduce hypoxia normally present in human bone marrow, using an innovative imaging technique to quantify oxygenation within 3D spheroids. We will test activity of standard chemotherapeutic drugs in breast cancer and promising molecularly-targeted compounds against human cell lines representative of intrinsic molecular subtypes of breast cancer integrated into 3D bone marrow spheroids. We also will test compounds against primary human breast cancer cells passaged only as mouse xenografts and correlate responses in 3D culture with patient outcomes. For both cell lines and primary tumor specimens, we will use advanced optical imaging methods to measure drug targeting, potential mechanisms of drug resistance, and heterogeneous responses of breast cancer cells to treatment. We will answer Provocative Question 17 by accomplishing the following specific aims: 1) develop an advanced 3D culture system to analyze treatment of disseminated human breast cancer cells in bone marrow; 2) quantify effects of compounds on breast cancer cell lines representative of molecular subclasses of human breast cancer and tumor-initiating cells; 3) determine activities of compounds against primary patient tumor samples. Collectively, this research will establish a facile, inexpensive, reproducible model to test potential cancer drugs and accurately match compounds with patient subpopulations highly likely to respond to treatment. The strategy will accelerate clinical translation of new, more effective cancer drugs while reducing costs of drug development.

描述（由申请人提供）：根据癌症研究界和 NCI 的确定，现有药物测试方法的低效和不准确是阻碍新药开发和临床转化以显着改善癌症治疗的关键障碍（挑衅性问题 17）。为了克服这些障碍，我们将开发一种新的骨髓微环境中播散性乳腺癌细胞的 3D 细胞培养模型。我们对骨髓微环境的关注是由于即使在看似局部原发性肿瘤的患者中，播散性癌细胞的频率很高，相对于原发性肿瘤而言，抗转移药物的活性有限，以及> 90％的癌症死亡率由转移性疾病引起。我们的模型将整合多种类型的人类骨髓基质细胞，包括间充质干细胞、内皮细胞和成骨细胞。这些细胞类型中的一种或多种形成保护性生态位，可以通过细胞间信号传导途径赋予转移性乳腺癌细胞耐药性。我们将优化培养条件，使用创新的成像技术来量化 3D 球体内的氧合，从而重现人类骨髓中通常存在的缺氧状态。我们将测试标准化疗药物在乳腺癌中的活性，以及针对代表乳腺癌内在分子亚型的人类细胞系的有前景的分子靶向化合物，并整合到 3D 骨髓球体中。我们还将测试针对仅作为小鼠异种移植物传代的原代人乳腺癌细胞的化合物，并将 3D 培养中的反应与患者结果相关联。对于细胞系和原发性肿瘤标本，我们将使用先进的光学成像方法来测量药物靶向、潜在的耐药机制以及乳腺癌细胞对治疗的异质反应。我们将通过实现以下具体目标来回答挑衅性问题 17：1）开发先进的 3D 培养系统来分析骨髓中播散性人类乳腺癌细胞的治疗； 2) 量化化合物对代表人乳腺癌分子亚类和肿瘤起始细胞的乳腺癌细胞系的影响； 3)确定化合物针对原发性患者肿瘤样品的活性。总的来说，这项研究将建立一个简便、廉价、可重复的模型来测试潜在的抗癌药物，并准确地将化合物与极有可能对治疗产生反应的患者亚群进行匹配。该战略将加速新的、更有效的癌症药物的临床转化，同时降低药物开发成本。