Kinase inhibitors created a new paradigm in chemotherapy and are a major focus of new oncology drug development. The Bcr-Abl inhibitor imatinib was a breakthrough drug for chronic myelogenous leukemia with overwhelming early results, however at least 30% of patients are either intolerant, resistant or experience recurrence within 1-5 years-and individual responses currently cannot be predicted at diagnosis. Overall survival is better for patients whose BCR- ABL/ABL1 mRNA ratio decreases 10-fold within 3-6 months, and pharmacodynamic response (actual inhibition of Bcr-Abl) by 28 days is a known indicator of achieving that-however, there is no current standard for testing pharmacodynamic response. This project will develop a companion diagnostic to measure Bcr-Abl activity and inhibition in a patient's own intact cells before and during treatment, in order t monitor the pharmacodynamics of imatinib and other kinase inhibitors in CML. This tool comprises a Bcr-Abl biosensor assay on the AssayMark microfluidic platform from Microfluidic Innovations, LLC, which is easy to use and generalizable to other kinases and cancers.
Specific aims : 1. Establish on-chip cell lysis to improve assay handling, 2. Develop chip designs for parallel assays and 3. Characterize technical figures of merit of the assay (e.g. analytical reproducibility) including pilot tests on deidentified patient samples. This will establish the bass for Phase II development of a companion diagnostic that will be compatible with the clinical laboratory.
This project will develop a companion diagnostic to measure Bcr-Abl activity and inhibition before and during treatment, in order to monitor the pharmacodynamics of imatinib and other kinase inhibitors in CML. This tool comprises a Bcr-Abl biosensor assay on a microfluidic platform that is easy to use and generalizable to other kinases and cancers.
