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, that can rapidly analyze the therapeutic response of a patients MM cells to various drugs in coculture with their own microenvironmental cell components. When MicroC3 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 and automate MicroC3 as a companion diagnostic for bortezomib, and other MM therapies. To achieve this project, Lynx Biosciences is uniquely positioned through four 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, 3) Salus Discovery, as a collaborator to develop an automated sample processing workflow, and 4) Microfluidic ChipShop, a manufacturing partner with years of experience in development and fabrication of microscale medical device platforms. The proposal consists of two aims: 1) To develop a GMP process for fabrication of injection molded MicroC3 devices, 2) To automate cell isolation, seeding, and treatment within MicroC3. At the conclusion of Phase I, we will have developed a large portion of the framework for the clinical rollout of the technology. We will have a reliable and robust process for both the fabrication and operation of the MicroC3 ready to handle the larger scale required for Phase II. Phase II will include a prospective clinical trial to test the predictive capabilities of MicroC3 by using the automated assay platform 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, identifying potentially successful preclinical drugs prior to initiation of clinical trials, and hematological malignancies other than MM.
Public Health Relevance Statement: Project Narrative Currently, many cancer patients, including multiple myeloma (MM) patients, are treated empirically, or with drug combinations based on their physicians 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 and automate 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; Air; aqueous; Automation; base; Biological Assay; Biological Sciences; Bone Marrow; Bone Marrow Cells; Bone Marrow Neoplasms; Bortezomib; Cancer Patient; cancer therapy; cell behavior; Cell Count; cell dimension; Cell Separation; Cell Survival; Cells; Cellular Structures; Clinical; Clinical Trials; Coculture Techniques; cohort; Collaborations; companion diagnostics; cost; Data; design; Development; Devices; Diffusion; Dimensions; Disease Progression; Disease Resistance; Drug Combinations; effective therapy; Employee Strikes; Exclusion; experience; Genus Lynx; Hematologic Neoplasms; Hematopoietic Neoplasms; individual patient; ineffective therapies; Injection of therapeutic agent; innovation; Legal patent; Liquid substance; Magnetism; Malignant Neoplasms; Measures; Medical Device; Microfluidic Microchips; Microfluidics; Molds; Multiple Myeloma; neoplastic cell; Oils; operation; Patients; Pharmaceutical Preparations; Phase; Physicians; Play; Population; population based; Positioning Attribute; pre-clinical; Preparation; Process; professor; programs; prospective; Protocols documentation; prototype; Refractory; Regimen; Relapse; relapse patients; Resistance; response; Retrospective Studies; Robot; Role; Sampling; Small Business Innovation Research Grant; Staging; Staining method; Stains; STAT3 gene; Technology; Testing; Therapeutic; therapy resistant; Time; tool; Toxic effect; treatment response; tumor; tumor microenvironment; Universities; Wisconsin
