?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.
Public Health Relevance Statement: PUBLIC HEALTH RELEVANCE Currently, many cancer patients, including multiple myeloma (MM) patients, are treated empirically, or with drug combinations based on their physician's experience and clinical trial data; it is impossible to predict which cancer therapies will be successful for individual patients. Cancer therapies, including MM therapies, are also very costly: >$10,000 per month with potentially significant side effects. In this proposal, we aim to develop an assay technology which enables clinicians to make more informed decisions regarding therapy course, utilize precious time more effectively, and reduce the cost associated with ineffective therapies.
Project Terms: Adverse effects; B lymphoid malignancy; base; Biological Assay; Biological Sciences; Bone Marrow; Bone Marrow Neoplasms; Bortezomib; calcein AM; Cancer Patient; cancer therapy; cancer type; Cell Count; cell dimension; Cells; Cellular Structures; Clinical; Clinical Trials; Coculture Techniques; Collaborations; companion diagnostics; cost; Cyclophosphamide; cytotoxicity; Data; design; Device Designs; Devices; Diffusion; Dimensions; Disease Progression; Disease Resistance; Dose; Drug Combinations; Dyes; effective therapy; ethidium homodimer; experience; Genus Lynx; Hematologic Neoplasms; Hematopoietic Neoplasms; individual patient; Injection of therapeutic agent; innovation; Legal patent; lenalidomide; Life; Malignant Neoplasms; Measures; Methods; Microfluidic Microchips; Microfluidics; Molds; Multiple Myeloma; neoplastic cell; Patients; Pharmaceutical Preparations; Phase; Physicians; Play; polydimethylsiloxane; Polystyrenes; population based; Positioning Attribute; pre-clinical; Process; professor; programs; prospective; Proteasome Inhibitor; public health relevance; Refractory; Relapse; Research Institute; Resistance; response; Role; Sample Size; Sampling; Sensitivity and Specificity; Small Business Innovation Research Grant; Staging; Staining method; Stains; standard of care; Techniques; Technology; Testing; Therapeutic; therapy resistant; Time; tool; Toxic effect; treatment response; tumor; tumor microenvironment; Universities; Validation; Wisconsin
