There is a critical unmet medical need for a rapid, accurate test to identify AML patients who are likely to respond to chemotherapy. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARAC) and idarubicin (IDR), known as 7+3, is the standard of care for most of these patients. However, 7+3 is a relatively ineffective therapy, particularly in older patients, and has serious therapyrelated toxicities. Accelerated Medical Diagnostics is developing the InductDx test to identify those patients whose AML will respond to 7+3 induction chemotherapy. The test utilizes ex vivo "diagnostic microdoses" (~1% of the therapeutic dose) of 14C-labeled ARA C and 14Clabeled IDR. Extremely low levels of 14C label are quantified in cancer cells isolated from patient blood samples using accelerator mass spectrometry (AMS). AMS is the most sensitive technology available for quantifying radiolabeled compounds in biological samples. We hypothesize that a threshold level of drugDNA damage is required for 7+3 efficacy, and the level of microdose-induced drug DNA damage is predictive of the capacity of AML cells to attain that threshold during in vivo chemotherapy. The extent of microdose-induced drug DNA damage in cell cultures and AML patient samples will be compared with cellular sensitivities and retrospective patient response to 7+3 therapy as proof-of concept for clinical development of the InductDx test for AML.
Public Health Relevance Statement: We propose to develop a rapid, clinically actionable ex vivo biomarker test to predict which AML patients will respond to cytarabine and idarubicin combination chemotherapy. This platform technology will enable improved treatment outcomes for AML and other cancers.
Project Terms: accelerator mass spectrometry; Acute Myelocytic Leukemia; Adult; Age-Years; Anthracyclines; Antimetabolites; Ara-C; Binding; Biological; Biological Markers; Blood; Blood specimen; Bone Marrow; cancer cell; Cell Culture Techniques; Cell Death; Cell Line; Cell-Mediated Cytolysis; Cells; chemotherapy; Chemotherapy-Oncologic Procedure; Clinical; clinical development; Clinical Research; clinically actionable; Combination Drug Therapy; companion diagnostics; Cytarabine; Death Rate; Development; Diagnosis; Diagnostic; Disease remission; DNA; DNA Damage; Dose; Doxorubicin; drug sensitivity; Drug Targeting; Funding; Goals; Idarubicin; improved; In Vitro; in vivo; ineffective therapies; innovation; Isotopes; Killings; Label; leukemia; Malignant Bone Neoplasm; Malignant Neoplasms; Measurable; Measurement; Measures; Mediating; Medical; Methods; Mononuclear; Myeloid Leukemia; older patient; Outcome; Pathologic; Patients; peripheral blood; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; predicting response; Primary Cell Cultures; Prior Chemotherapy; prospective; Protocols documentation; Radiolabeled; Regimen; Resistance; response; Sampling; Small Business Innovation Research Grant; standard of care; Surrogate Endpoint; Technology; Testing; Therapeutic; Time; Toxic effect; Treatment outcome; trend; United States; uptake; Whole Blood
