A biochemical companion diagnostic platform to measure kinase inhibitor pharmacodynamics in leukemia

DESCRIPTION provided by applicant 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 of patients are either intolerant resistant or experience recurrence within years and individual responses currently cannot be predicted at diagnosis Overall survival is better for patients whose BCR ABL ABL mRNA ratio decreases fold within months and pharmacodynamic response actual inhibition of Bcr Abl by 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 patientandapos 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 Establish on chip cell lysis to improve assay handling Develop chip designs for parallel assays and 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

PUBLIC HEALTH RELEVANCE 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