Microfluidic assay to predict patient-specific multiple myeloma clinical response

微流控检测预测患者特异性多发性骨髓瘤临床反应

• 批准号: 9048255
• 负责人: Chorom Pak
• 金额: $ 26.88万
• 依托单位: LYNX BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9048255
• 关键词: Adverse effects; B lymphoid malignancy; Biological Assay; Biological Sciences; Bone Marrow; Bone Marrow Neoplasms; Bortezomib; Cancer Patient; Cell Count; Cells; Cellular Structures; Clinical; Clinical Trials; Coculture Techniques; Collaborations; Cyclophosphamide; Data; Device Designs; Devices; Diffusion; Dimensions; Disease Progression; Disease Resistance; Dose; Drug Combinations; Dyes; Genus Lynx; Hematologic Neoplasms; Hematopoietic Neoplasms; Injection of therapeutic agent; Legal patent; Life; Malignant Neoplasms; Measures; Methods; Microfluidic Microchips; Microfluidics; Molds; Multiple Myeloma; Patients; Pharmaceutical Preparations; Phase; Physicians; Play; Polystyrenes; Positioning Attribute; Process; Proteasome Inhibitor; Refractory; Relapse; Research Institute; Resistance; Role; Sample Size; Sampling; Sensitivity and Specificity; Small Business Innovation Research Grant; Staging; Staining method; Stains; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; Universities; Validation; Wisconsin; base; calcein AM; cancer therapy; cancer type; cell dimension; companion diagnostics; cost; cytotoxicity; design; effective therapy; ethidium homodimer; experience; individual patient; ineffective therapies; innovation; lenalidomide; neoplastic cell; polydimethylsiloxane; population based; pre-clinical; professor; programs; prospective; public health relevance; response; standard of care; therapy resistant; tool; treatment response; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant) Multiple myeloma (MM) is a debilitating and currently incurable hematological malignancy. While the median survival has increased to 5 - 7 years, MM patients ultimately relapse and become resistant to therapy. Once they reach this stage, it is often a trial and error process until an effective therapy can be found. Furthermore, the MM bone marrow tumor microenvironment plays a significant role in disease progression and resistance to therapy. There is a critical need for a clinical tool able to predict therapeutic response to drugs for specific patients. We have developed an ex vivo microfluidic platform, MicroC3(tm) , that can rapidly analyze the therapeutic response of a patient's MM cells to various drugs in coculture with their own microenvironmental cell components. When MicroC3(tm) was initially tested by measuring the ex vivo toxicity responses of patient MM cells to bortezomib, a drug commonly used in MM therapy, MicroC3 responses could be segregated into two groups which retrospectively correctly identified all patients as either clinically responsive or non-responsive to bortezomib-containing therapies. We propose to develop MicroC3 as a companion diagnostic (CD) for bortezomib, and other MM therapies. To achieve this project, Lynx Biosciences is uniquely positioned through three key collaborations: 1) Dr. Natalie Callander as a collaborator and Director of the University of Wisconsin Myeloma Clinical Program, 2) Professor David Beebe as an expert consultant and pioneer of simple microfluidic devices, and 3) the Morgridge Institutes for Research, enabling Lynx to have direct access to prototyping facilities and experts in device design for manufacturability. The proposal consists of two aims: 1) Standardize bonding and fabrication of the MicroC3 device by changing the material it is currently fabricated of to polystyrene (PS) in order to accommodate testing of all drugs and facilitate high-throughput fabrication. 2) Initiate a small clinical trial of 20 patientswho will be receiving bortezomib-containing therapies as standard of care, and comparing their clinical responses to ex vivo MicroC3 responses to bortezomib. Using the same samples from these 20 patients, we will also assess ex vivo responses to cyclophosphamide and lenalidomide (two drugs commonly used in combination with bortezomib) to determine the optimal dose at which to segregate their ex vivo responses. At the conclusion of Phase I, the sensitivity/specificity of MicroC3 as a proof- of-concept CD for bortezomib will have been determined. This will allow us to calculate the sample size of a prospective clinical trial in Phas II to test the predictive capabilities of MicroC3 by using the PS devices to segregate patients for therapy containing bortezomib and potentially other therapies. Ultimately, MicroC3 may be applied for use in reviving drugs which were not successful in late stage clinical trials, identifyng potentially successful preclinical drugs prior to initiation of clinical trials, and hematological malignancies other than MM.

 描述（由申请人提供）多发性骨髓瘤（MM）是一种使人衰弱且目前无法治愈的血液恶性肿瘤。虽然中位生存期已增加到5 - 7年，但MM患者最终复发并对治疗产生耐药性。一旦他们到达这个阶段，它往往是一个试验和错误的过程，直到一个有效的治疗方法可以找到。此外，MM骨髓肿瘤微环境在疾病进展和治疗抵抗中起着重要作用。迫切需要一种能够预测特定患者对药物的治疗反应的临床工具。我们已经开发了一种离体微流体平台MicroC 3（tm），它可以快速分析患者MM细胞对与其自身微环境细胞组分共培养的各种药物的治疗反应。当最初通过测量患者MM细胞对硼替佐米（一种MM治疗中常用的药物）的离体毒性反应来测试MicroC 3（TM）时，MicroC 3反应可以分为两组，这两组回顾性地正确鉴定了所有患者对含硼替佐米的治疗的临床反应或无反应。我们建议开发MicroC 3作为硼替佐米和其他MM疗法的伴随诊断（CD）。为了实现这一项目，Lynx Biosciences通过三个关键合作进行了独特定位：1）娜塔莉卡兰德博士作为合作者和威斯康星州大学骨髓瘤临床项目主任，2）大卫毕比教授作为专家顾问和简单微流体设备的先驱，3）莫格里奇研究所，使Lynx能够直接接触到原型制造设施和可制造性设备设计专家。该提案包括 两个目标：1）通过将目前制造MicroC 3设备的材料改为聚苯乙烯（PS）来标准化MicroC 3设备的粘合和制造，以适应所有药物的测试并促进高通量制造。2)启动一项20名患者的小型临床试验，这些患者将接受含硼替佐米的治疗作为标准治疗，并将其临床反应与体外MicroC 3对硼替佐米的反应进行比较。使用来自这20名患者的相同样本，我们还将评估对环磷酰胺和来那度胺（两种常与硼替佐米联合使用的药物）的离体反应，以确定分离其离体反应的最佳剂量。在I期结束时，将确定MicroC 3作为硼替佐米概念验证CD的灵敏度/特异性。这将使我们能够计算Phas II中前瞻性临床试验的样本量，以通过使用PS器械隔离患者来测试MicroC 3的预测能力， 含有硼替佐米的疗法和可能的其它疗法。最终，MicroC 3可用于恢复在后期临床试验中不成功的药物，在临床试验开始前识别潜在成功的临床前药物，以及MM以外的血液恶性肿瘤。