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Therapeutic effect of TRC105 and decitabine combination in AML xenografts

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The hypomethylating agent decitabine (DAC) is an alternative treatment for elderly and relapsed/refractory AML patients, yet responses following DAC monot...

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Autores principales: Baik, June, Felices, Martin, Yingst, Ashley, Theuer, Charles P., Verneris, Michael R., Miller, Jeffrey S., Perlingeiro, Rita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566100/
https://www.ncbi.nlm.nih.gov/pubmed/33088975
http://dx.doi.org/10.1016/j.heliyon.2020.e05242
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author Baik, June
Felices, Martin
Yingst, Ashley
Theuer, Charles P.
Verneris, Michael R.
Miller, Jeffrey S.
Perlingeiro, Rita
author_facet Baik, June
Felices, Martin
Yingst, Ashley
Theuer, Charles P.
Verneris, Michael R.
Miller, Jeffrey S.
Perlingeiro, Rita
author_sort Baik, June
collection PubMed
description Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The hypomethylating agent decitabine (DAC) is an alternative treatment for elderly and relapsed/refractory AML patients, yet responses following DAC monotherapy are still modest. The transforming growth factor-β (TGF-β) receptor CD105 (endoglin) is expressed in various hematopoietic malignancies, and high CD105 expression correlates with poor prognosis in AML patients. Using a xenograft model, we have recently demonstrated that targeting CD105(+) AML blasts with the TRC105 monoclonal antibody inhibits leukemia progression. Here we investigated whether administration of TRC105 along with DAC could represent a novel therapeutic option for relapsed/refractory AML. Our data show that the DAC/TRC105 combination results in a more durable anti-leukemic effect in AML xenografts compared to DAC monotherapy. Moreover, the DAC/TRC105 combination enhanced reactive oxygen species (ROS) activity, which correlated with reduced leukemia burden. RNA-sequencing studies suggest that TRC105 may alter TGF-β activity in AML blasts. Taken together, these findings provide rationale for the clinical evaluation of TRC105 in combination with DAC in AML patients.
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spelling pubmed-75661002020-10-20 Therapeutic effect of TRC105 and decitabine combination in AML xenografts Baik, June Felices, Martin Yingst, Ashley Theuer, Charles P. Verneris, Michael R. Miller, Jeffrey S. Perlingeiro, Rita Heliyon Research Article Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The hypomethylating agent decitabine (DAC) is an alternative treatment for elderly and relapsed/refractory AML patients, yet responses following DAC monotherapy are still modest. The transforming growth factor-β (TGF-β) receptor CD105 (endoglin) is expressed in various hematopoietic malignancies, and high CD105 expression correlates with poor prognosis in AML patients. Using a xenograft model, we have recently demonstrated that targeting CD105(+) AML blasts with the TRC105 monoclonal antibody inhibits leukemia progression. Here we investigated whether administration of TRC105 along with DAC could represent a novel therapeutic option for relapsed/refractory AML. Our data show that the DAC/TRC105 combination results in a more durable anti-leukemic effect in AML xenografts compared to DAC monotherapy. Moreover, the DAC/TRC105 combination enhanced reactive oxygen species (ROS) activity, which correlated with reduced leukemia burden. RNA-sequencing studies suggest that TRC105 may alter TGF-β activity in AML blasts. Taken together, these findings provide rationale for the clinical evaluation of TRC105 in combination with DAC in AML patients. Elsevier 2020-10-13 /pmc/articles/PMC7566100/ /pubmed/33088975 http://dx.doi.org/10.1016/j.heliyon.2020.e05242 Text en © 2020 The Authors. Published by Elsevier Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Baik, June
Felices, Martin
Yingst, Ashley
Theuer, Charles P.
Verneris, Michael R.
Miller, Jeffrey S.
Perlingeiro, Rita
Therapeutic effect of TRC105 and decitabine combination in AML xenografts
title Therapeutic effect of TRC105 and decitabine combination in AML xenografts
title_full Therapeutic effect of TRC105 and decitabine combination in AML xenografts
title_fullStr Therapeutic effect of TRC105 and decitabine combination in AML xenografts
title_full_unstemmed Therapeutic effect of TRC105 and decitabine combination in AML xenografts
title_short Therapeutic effect of TRC105 and decitabine combination in AML xenografts
title_sort therapeutic effect of trc105 and decitabine combination in aml xenografts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566100/
https://www.ncbi.nlm.nih.gov/pubmed/33088975
http://dx.doi.org/10.1016/j.heliyon.2020.e05242
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