Rapid Testing of Drug-Resistant BCR-ABL(+)Leukemia Cells

耐药 BCR-ABL( )白血病细胞的快速检测

• 批准号: 8121144
• 负责人: Ronald J Rieder
• 金额: $ 19.97万
• 依托单位: BIOSENSE TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2013-05-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121144
• 关键词: Address; Apoptotic; Autophagocytosis; Biological; Biological Assay; Biopsy Specimen; Biosensing Techniques; Blood; Blood specimen; Bone Marrow; Cell Adhesion; Cell Culture Techniques; Cell Death; Cell Line; Cell Survival; Cells; Cellular Stress; Cessation of life; Chemosensitivity Assay; Chronic Myeloid Leukemia; Clinical; Complex; Dasatinib; Development; Diagnostic; Drug resistance; Drug-sensitive; Electric Capacitance; Electronics; Exposure to; Extracellular Matrix; Generations; Growth; Human; Imatinib mesylate; Knowledge; Leukocytes; Malignant Neoplasms; Marrow; Measures; Medicine; Metabolic Pathway; Metabolism; Methods; Modality; Modification; Monitor; Myelogenous; Necrosis; Oncologist; Outcome; Patients; Pharmaceutical Preparations; Phase; Property; Protein Tyrosine Kinase; Research; Resistance; Resistance profile; Sampling; Sensitivity and Specificity; Signal Transduction; Solid Neoplasm; Stress; Suspension substance; Suspensions; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Treatment Failure; Tyrosine Kinase Inhibitor; arm; base; bcr-abl Fusion Proteins; biological adaptation to stress; cancer cell; cancer therapy; cancer type; cell growth; cell type; clinical application; drug sensitivity; effective therapy; electric impedance; improved; instrumentation; leukemia; novel diagnostics; protocol development; prototype; research clinical testing; response; time use; tool

DESCRIPTION (provided by applicant): Resistance to chemotherapeutic drugs is an ongoing problem that results in eventual treatment failures or suboptimal patient outcomes. In cancer cells treated with drugs to which they are sensitive, the stress response is the first step in the subsequent cascade leading to cell death (apoptotic, necrotic or autophagy). The recent availability of a sensing modality for monitoring the development of stress in viable cells makes possible the utilization of stress as a diagnostic tool. BioSense Technologies proposes the development of a new diagnostic assay to determine the chemosensitivity of BCR-ABL (+) leukemia cells to therapeutic agents in real-time using unprocessed blood or bone marrow samples. Because the initiation of the stress response is immediate, drug-resistant leukemia cells can be distinguished from drug-sensitive cells in real- time avoiding any need for traditional cell culture to obtain the same information. This ability to provide the most effective therapy for each patient will reduce treatment failures and result in overall improved patient outcomes. Importantly, because the approach monitors a property fundamental to all cells, it is directly applicable to all other cancer cells types including solid tumor cancers. Feasibility of the proposed approach will be demonstrated with established human myeloid and lymphoblastic (Ph+) cell lines both drug-sensitive and -resistant to tyrosine kinase inhibitors. A follow-on effort will focus on the development of prototype instrumentation and validate the approach through clinical testing. PUBLIC HEALTH RELEVANCE: The development of a real-time diagnostic tool for determining the sensitivity/resistance profiles of leukemia cells to therapeutic agents is a significant step towards the administration of personalized medicine and optimal patient outcomes. By addressing and overcoming a significant technical barrier (the ability to determine the effects of a therapeutic agent on a cancer cell rapidly) the proposed project enables drug-resistant cancer cells to be distinguished from drug-sensitive cells in real-time. The availability of this diagnostic tool will arm oncologists with knowledge on the most effective drugs for eliminating the cancer cells as well as monitoring the possible onset of drug resistance during the administration of treatment. These new capabilities will avoid the empirical prescription of cancer therapy and enable the start or modification of existing treatment choices as needed. While the technical approach is applicable to a spectrum of different cancer types and therapeutic agents, this project focuses on the chemosensitivity testing of leukemia cells to tyrosine kinase inhibiting agents and the identification of drug resistance as an initial demonstration of its feasibility.

描述（由申请人提供）：对化疗药物的耐药性是一个持续存在的问题，会导致最终治疗失败或患者结果不佳。在用对其敏感的药物治疗的癌细胞中，应激反应是导致细胞死亡（凋亡、坏死或自噬）的后续级联反应的第一步。最近出现的用于监测活细胞中应激发展的传感方式使得利用应激作为诊断工具成为可能。 BioSense Technologies 提议开发一种新的诊断检测方法，利用未处理的血液或骨髓样本实时确定 BCR-ABL (+) 白血病细胞对治疗药物的化学敏感性。由于应激反应立即启动，因此可以实时区分耐药白血病细胞和药物敏感细胞，而无需传统的细胞培养来获得相同的信息。这种为每位患者提供最有效治疗的能力将减少治疗失败并整体改善患者的治疗效果。重要的是，由于该方法监测所有细胞的基本特性，因此它可直接适用于包括实体瘤在内的所有其他癌细胞类型。所提出方法的可行性将通过已建立的对药物敏感且对酪氨酸激酶抑制剂具有抗性的人骨髓和淋巴母细胞（Ph+）细胞系来证明。后续工作将集中于原型仪器的开发并通过临床测试验证该方法。 公共卫生相关性：开发用于确定白血病细胞对治疗药物的敏感性/耐药性的实时诊断工具是迈向个性化医疗和最佳患者治疗结果的重要一步。通过解决和克服一个重大的技术障碍（快速确定治疗剂对癌细胞的影响的能力），拟议的项目能够实时区分耐药癌细胞与药物敏感细胞。这种诊断工具的出现将使肿瘤学家掌握消除癌细胞最有效药物的知识，并监测治疗期间可能出现的耐药性。这些新功能将避免癌症治疗的经验处方，并能够根据需要启动或修改现有的治疗选择。虽然该技术方法适用于一系列不同的癌症类型和治疗药物，但该项目的重点是白血病细胞对酪氨酸激酶抑制剂的化学敏感性测试以及耐药性的鉴定，作为其可行性的初步证明。