Abstract
BackgroundAcute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here, we show the results of our preclinical study, in which we evaluated the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT).Methods and Resultsfb-PMT (NP751) is a potent αvβ3 antagonist of molecular weight of 2,478.9 Da. it represents a conjugate of tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol (PEG36), with a 4-fluorobenzyl group capping the other end of the PEG. fb-PMT effectively suppresses the malignant growth of human acute myeloid leukemia (AML) after successful engraftment in transgenic NSG-S xenograft mouse models of either established human AML cell line or primary AML cells. Daily treatment with fb-PMT (1–10 mg/kg body weight) subcutaneously (s.c.) for 3–4 weeks was associated with marked regression of leukemogenesis and extended survival in both models. The efficiency of the fb-PMT therapy was verified using in vivo imaging system (IVIS) imaging, flow cytometry, and histopathological examination to monitor the engraftment of leukemic cells in the bone marrow and other organs. fb-PMT therapy for 3–4 weeks at 3 and 10 mg/kg daily doses exhibited significant reduction (p < 0.0001) of leukemic cell burden of 74% and >95%, respectively. All fb-PMT-treated mice in the 10 mg/kg treatment arm successfully maintained remission after discontinuing the daily treatment. Comprehensive fb-PMT safety assessments demonstrated excellent safety and tolerability at multiple folds above the anticipated human therapeutic doses. Lastly, our genome-wide microarray screens demonstrated that fb-PMT works through the molecular interference mechanism with multiple signaling pathways contributing to growth and survival of leukemic cells.ConclusionOur preclinical findings of the potent anticancer activities of fb-PMT and its favorable safety profiles warrant its clinical investigation for the effective and safe management of AML.
Highlights
Acute myeloid leukemia (AML) is one of the most aggressive malignant hematological disorders
This study focused on comprehensive preclinical evaluations of anticancer activities of a novel thyrointegrin avb[3] antagonist, Fluorobenzyl polyethylene glycol mono-triazole tetraiodothyroacetic acid (fb-PMT) in models of AML
Effects of fb-PMT Therapy on K562-Luc Human Leukemic Cell Line and FLT3-ITD Primary Human AML Cells Engrafted in Transgenic Mice In the K562-Luc engrafted in transgenic mice, blast cells appeared in the blood smears of NSG-S mice 10 days after engraftment, with an average value of 40%
Summary
Acute myeloid leukemia (AML) is one of the most aggressive malignant hematological disorders. In 2021, the estimated number of deaths from AML is 11,400, which represents 56.32% of new cases (1.0% of all cancer deaths), with an overall 5-year survival rate of 27%. Current treatment regimens for AML include traditional chemotherapy, allogeneic hematopoietic cell transplantation, and targeted therapies for specific mutations in limited numbers of AML patients [e.g., Midostaurin, a FLT3 inhibitor, first gene mutation-targeted therapeutic agent approved by Food and Drug Administration (FDA) 2017], all of whom still suffer from adverse effects and relapse (2, 3). New broad spectrum effective and safe treatment options are urgently needed for the different types of AML. Acute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. We show the results of our preclinical study, in which we evaluated the efficacy of a new thyrointegrin avb[3] antagonist, named fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT)
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