AUTHOR=Darwish Noureldien H. E. , Glinsky Gennadi V. , Sudha Thangirala , Mousa Shaker A. 

TITLE=Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia

JOURNAL=Frontiers in Oncology

VOLUME=Volume 11 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.793810

DOI=10.3389/fonc.2021.793810

ISSN=2234-943X

ABSTRACT=Background: Acute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here we show the results of our pre-clinical study, in which we evaluate the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl Polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT). 
Methods and Results: 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 IVIS imaging, flowcytometry 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. 
Conclusion: our 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.