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（由适用的）多发性骨髓瘤（MM）是一种令人衰弱的且目前无法治愈的血液恶性肿瘤。虽然中位生存率已增加到5 - 7年，但MM患者最终会中继并对治疗具有抵抗力。一旦到达这个阶段，通常是一个试验和错误过程，直到找到有效的治疗。此外，MM骨髓肿瘤微环境在疾病进展和对治疗的抵抗力中起着重要作用。对于可以预测特定患者药物治疗反应的临床工具的迫切需要。我们已经开发了一个离体微流体平台Microc3（TM），该平台可以快速分析患者的MM细胞对各种药物在共培养中使用其自身微环境细胞成分的治疗反应。当最初通过测量患者MM细胞对Bortezomib的过时毒性反应来测试MicroC3（TM）（TM）时，通常用于MM治疗中的一种药物时，MicroC3反应可以被循环地分离为两组，这些反应将所有患者正确地鉴定为临床反应型或对Bortezomib-Conteezomib-contepontemib conteage contecties the ther the ther the ther the bortsips the bortepy毒性。我们建议将MicroC3作为硼替佐米和其他MM疗法的伴侣诊断（CD）。 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用于制造的设备设计。该提议包括 两个目的：1）通过更改当前制造的聚苯乙烯（PS）的材料来标准化Microc3设备的键合和制造，以适应所有药物的测试并促进高通量制造。 2）对20例患者进行一项小型临床试验，他们将接受辅助硼替佐米的疗法作为护理标准，并将其临床反应与离体Microc3对硼替佐米的反应进行比较。使用来自这20名患者的相同样品，我们还将评估对环磷酰胺和来纳略胺（与硼替佐米结合使用的两种药物）的离体反应，以确定其在该剂量上分离其离体反应的最佳剂量。在第I阶段结束时，将确定MicroC3作为概念验证CD的灵敏度/特异性。这将使我们能够通过使用PS设备将患者隔离以隔离患者的PHAS II中的前瞻性临床试验样本量，以测试MICROC3的预测能力 含有硼替佐米和其他疗法的疗法。最终，MicroC3可用于用于在晚期临床试验中未成功的恢复药物，在开始临床试验之前确定潜在成功的临床前药物，以及除MM以外的血液学恶性肿瘤。