Work

A Novel Fluorobenzyl Polyethylene Glycol Conjucated Tetraiodothyroacetic Acid (fb-PMT), Targeting Thyrointegrin αvβ3 in Treatment Acute Myeloid Leukemia

Year: 2021

Type: preprint

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 conjucated 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.

Source: Research Square

DOI: 10.21203/rs.3.rs-754222/v1

Authors: Noureldien H. E. Darwish, Gennadi V. Glinsky, Thangirala Sudha, Shaker A. Mousa

Institutions: Albany College of Pharmacy and Health Sciences, ORCID, University of California San Diego

Language: English

Topic: Acute Myeloid Leukemia Research

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: State University of New York, University at Albany