SBIR-STTR Award

Resistance to chemotherapeutic drugs is an ongoing problem that results in eventual treatment failures or suboptimal patient outcomes. In cancer cells treated with drugs to which they are sensitive, the stress response is the first step in the subsequent cascade leading to cell death (apoptotic, necrotic or autophagy). The recent availability of a sensing modality for monitoring the development of stress in viable cells makes possible the utilization of stress as a diagnostic tool. BioSense Technologies proposes the development of a new diagnostic assay to determine the chemosensitivity of BCR-ABL (+) leukemia cells to therapeutic agents in real-time using unprocessed blood or bone marrow samples. Because the initiation of the stress response is immediate, drug-resistant leukemia cells can be distinguished from drug-sensitive cells in real- time avoiding any need for traditional cell culture to obtain the same information. This ability to provide the most effective therapy for each patient will reduce treatment failures and result in overall improved patient outcomes. Importantly, because the approach monitors a property fundamental to all cells, it is directly applicable to all other cancer cells types including solid tumor cancers. Feasibility of the proposed approach will be demonstrated with established human myeloid and lymphoblastic (Ph+) cell lines both drug-sensitive and -resistant to tyrosine kinase inhibitors. A follow-on effort will focus on the development of prototype instrumentation and validate the approach through clinical testing.

Public Health Relevance:
The development of a real-time 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 a cancer cell rapidly) the proposed project enables drug-resistant cancer cells to be distinguished from drug-sensitive cells in real-time. The availability of this diagnostic tool will arm oncologists with knowledge on the most effective drugs for eliminating the cancer cells as well as monitoring the possible 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 the technical approach is applicable to a spectrum of different cancer types and therapeutic agents, 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.

Thesaurus Terms:
Address;Apoptotic;Assay;Autophagocytosis;Bcr-Abl;Bcr-Abl Oncoprotein;Bcr-Abl Protein Tyrosine Kinase;Bcr/Abl;Bioassay;Biologic Assays;Biological;Biological Assay;Biopsy Sample;Biopsy Specimen;Biosensing Technics;Biosensing Techniques;Blood;Blood (Leukemia);Blood Reticuloendothelial System;Blood Sample;Blood Leukocyte;Blood Specimen;Bone Marrow;Bone Marrow Reticuloendothelial System;Cancer Treatment;Cancers;Cell Adhesion;Cell Communication And Signaling;Cell Culture Techniques;Cell Death;Cell Line;Cell Signaling;Cell Survival;Cell Viability;Cell-Extracellular Matrix;Cellline;Cells;Cellular Adhesion;Cellular Expansion;Cellular Growth;Cellular Stress;Cessation Of Life;Chemosensitivity Assay;Chemosensitivity Testing;Chronic Myelocytic Leukemia;Chronic Myelogenous Leukemia;Chronic Myeloid Leukemia;Clinical;Clinical Evaluation;Clinical Testing;Complex;Dasatinib;Death;Development;Diagnostic;Drug Resistance;Drug-Sensitive;Drugs;Ecm;Eph- And Elk-Related Tyrosine Kinase;Eph-And Elk-Related Kinase;Electric Capacitance;Electrical Capacitance;Electrical Impedance;Electronics;Ephrin Type-A Receptor 8;Ephrin Type-A Receptor 8 Precursor;Exposure To;Extracellular Matrix;Generalized Growth;Generations;Growth;Human;Imatinib Mesylate;Impedance;Intermediary Metabolism;Intracellular Communication And Signaling;Knowledge;Loinc Axis 2 Property;Leukemia, Granulocytic, Chronic;Leukocytes;Leukocytes Reticuloendothelial System;Malignant Cell;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Neoplasms;Malignant Tumor;Man (Taxonomy);Marrow;Marrow Leukocyte;Measures;Medication;Medicine;Metabolic Pathway;Metabolic Processes;Metabolism;Methods;Modality;Modern Man;Modification;Monitor;Myelogenous;Myeloid;Necrosis;Necrotic;Oncologist;Outcome;Ptk Inhibitors;Patients;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Property;Protein Tyrosine Kinase;Protein Tyrosine Kinase Eek;Protein Tyrosine Kinase Inhibitors;Research;Resistance;Resistance Profile;Resistant Profile;Sampling;Sensitivity And Specificity;Signal Transduction;Signal Transduction Systems;Signaling;Solid Neoplasm;Solid Tumor;Strains Cell Lines;Stress;Suspension Substance;Suspensions;Tk Inhibitors;Techniques;Technology;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Growth;Treatment Failure;Tyrosine Kinase;Tyrosine Kinase Inhibitor;Tyrosine-Protein Kinase Receptor Eek;Tyrosine-Specific Protein Kinase;Tyrosylprotein Kinase;White Blood Cells;White Cell;Anticancer Therapy;Arm;Autophagy;Base;Bcr-Abl Fusion Proteins;Biological Adaptation To Stress;Biological Signal Transduction;Biosensing;Cancer Cell;Cancer Therapy;Cancer Type;Capacitance;Cell Culture;Cell Growth;Cell Stress;Cell Type;Clinical Applicability;Clinical Application;Clinical Test;Cultured Cell Line;Developmental;Drug Resistant;Drug Sensitivity;Drug/Agent;Effective Therapy;Effective Treatment;Electric Impedance;Hydroxyaryl Protein Kinase;Improved;Instrumentation;Leukemia;Malignancy;Necrocytosis;Neoplasm/Cancer;New Diagnostics;Next Generation Diagnostics;Novel Diagnostics;Ontogeny;Protocol Development;Prototype;Reaction;Crisis;Research Clinical Testing;Resistance To Drug;Resistant;Resistant To Drug;Response;Stress Response;Stress;Reaction;Suspension;Time Use;Tool;Tyrosyl Protein Kinase;White Blood Cell;White Blood Corpuscle

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.

Public Health Relevance Statement:


Public Health Relevance:
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.

NIH Spending Category:
Bioengineering; Cancer; Hematology; Orphan Drug; Rare Diseases

Project Terms:
Address; Aftercare; Animal Model; Animals; Apoptotic; arm; Autophagocytosis; base; bcr-abl Fusion Proteins; Biological Assay; Biosensing Techniques; Blood; Blood specimen; Calculi; cancer cell; Cancer Patient; cancer therapy; cancer type; Cell Death; Cell Line; Cell physiology; Cells; Cellular Stress; Chemosensitivity Assay; Chronic; Chronic Myeloid Leukemia; Clinical; clinically relevant; Collaborations; compare effectiveness; Complex; cost; Dana-Farber Cancer Institute; Dasatinib; Development; Diagnosis; Diagnostic; Drug resistance; drug sensitivity; Drug-sensitive; Effectiveness; electric impedance; Exposure to; FLT3 gene; Foundations; Generations; Germ Cells; Human; Imatinib mesylate; improved; instrumentation; Investigation; Killings; Knowledge; leukemia; Leukemia, Lymphocytic, Acute; Malignant Neoplasms; Marrow; Measurement; Measures; Medicine; Metabolism; Methods; Modality; Modification; Monitor; mouse model; Necrosis; novel; Oncogenes; Oncologist; Outcome; Patients; peripheral blood; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Population; Protein Tyrosine Kinase; prototype; public health relevance; Reproducibility; Research; Resistance; Resistance profile; response; Sampling; Stem cells; Stress; success; Suspension substance; Suspensions; Technology; Testing; Therapeutic Agents; tool; Treatment Failure; Tyrosine Kinase Inhibitor