Resistance to chemotherapeutic drugs is an ongoing problem that results in eventual treatment failures or suboptimal patient outcomes. Approximately one-quarter of BCR-ABL(+) leukemia patients demonstrate evidence of resistance to imatinib mesylate either at initial diagnosis or at some point after treatment has begun. In our Phase I investigation, we demonstrated that monitoring the cellular stress developed by BCR-ABL(+) leukemia cells in response to tyrosine kinase inhibiting (TKI) drugs can used as an early marker for determining the effect of the therapeutic agents on the cancer cells. The approach is optimally implemented by measuring the dielectric permittivity of drug-treated cell suspensions using differential impedance sensing. Corresponding measurements of drug-sensitive and drug-resistant BCR-ABL(+) cell lines were obtained and confirmed by MTT assay. The response of non-leukemic peripheral blood mononuclear cells (PBMCs) to TKIs measured at clinically relevant drug concentrations showed no significant background level. Finally, the responses of BCR-ABL(+) patient blood to different TKIs were consistent with our initial cell line measurements laying the foundation for a practical clinical assay. In this Phase I effort we propose to quantify the cellular stress related drug responses enabling ease in interpretation of results, develop prototype instrumentation, verify the technical approach through animal model measurements and demonstrate feasibility with patient samples.
The development of a rapid diagnostic tool for determining the sensitivity/resistance profiles of leukemia cells to therapeutic agents is a significant step towards the administration of personalized medicine and optimal patient outcomes. By addressing and overcoming a significant technical barrier (the ability to determine the effects of a therapeutic agent on difficult to culture cancer cells), the proposed project enables drug-resistant cancer cells to be distinguished from drug-sensitive cells easily and rapidly. The availability of this diagnostic tool will arm oncologists with knowledge of the most effective drug for eliminating the cancer cells and the ability to monitor the onset of drug resistance during the administration of treatment. These new capabilities will avoid the empirical prescription of cancer therapy and enable the start or modification of existing treatment choices as needed. While this project focuses on the chemosensitivity testing of leukemia cells to tyrosine kinase inhibiting agents and the identification of drug resistance as an initial demonstration of its feasibility, the technical approach is applicable to a spectrum of different cancer types and therapeutic agents.
