Microfluidic assay to predict patient-specific multiple myeloma clinical response

 描述(申请人提供)多发性骨髓瘤(MM)是一种衰弱的，目前无法治愈的血液系统恶性肿瘤。虽然中位生存期增加到5-7年，但多发性骨髓瘤患者最终会复发并对治疗产生抵抗力。一旦达到这个阶段，在找到有效的治疗方法之前，这通常是一个反复尝试的过程。此外，多发性骨髓瘤的微环境在疾病进展和对治疗的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。我们已经开发了一个体外微流控平台MicroC3(Tm)，它可以快速分析患者的MM细胞在与自身微环境细胞成分共同培养的情况下对各种药物的治疗反应。当通过测量患者MM细胞对多发性骨髓瘤治疗常用药物Bortezomib的体外毒性反应来测试MicroC3(Tm)时，MicroC3的反应可以分为两组，这两组患者回顾性地正确地识别出所有患者对含有Bortezomib的治疗有反应或无反应。我们建议开发MicroC3作为Bortezomib和其他MM疗法的辅助诊断(CD)。为了实现这一项目，Lynx Biosciences通过三个关键合作项目处于独特的地位：1)Natalie Callander博士是威斯康星大学骨髓瘤临床项目的合作者和主任，2)David Beebe教授是简单微流体设备的专家顾问和先驱，3)摩格里奇研究所，使Lynx能够直接接触到原型设施和设备设计方面的专家，以实现可制造性。该提案包括 两个目标：1)通过将目前制造MicroC3设备的材料改为聚苯乙烯(PS)来标准化键合和制造，以适应所有药物的测试并促进高通量制造。2)启动一项小型临床试验，将20名患者作为标准治疗，接受含有Bortezomib的治疗，并比较他们对体外MicroC3对Bortezomib反应的临床反应。使用来自这20名患者的相同样本，我们还将评估环磷酰胺和来那度胺(两种药物通常与硼替佐米联合使用)的体外反应，以确定分离他们的体外反应的最佳剂量。在第一阶段结束时，将确定MicroC3作为对Bortezomib的概念验证CD的敏感性/特异性。这将使我们能够计算PHAS II的前瞻性临床试验的样本量，以通过使用PS设备将患者分离出来测试MicroC3的预测能力 包含波特佐米和可能的其他疗法的疗法。最终，MicroC3可用于复苏在临床试验晚期失败的药物，在临床试验开始前识别潜在成功的临床前药物，以及MM以外的血液系统恶性肿瘤。

 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.