Therapeutic effect of TRC105 and decitabine combination in AML xenografts

Abstract

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.

Curcuminoids Inhibit Angiogenic Behaviors of Human Umbilical Vein Endothelial Cells via Endoglin/Smad1 Signaling

“…Combination treatment with an endoglin antagonist and VEGF antagonist enhances the inhibition of HUVEC angiogenesis, which overcomes drug resistance to VEGF-neutralizing agents. Combination therapy with TRC105 and decitabine provides a sustained anti-leukemic impact in acute myeloid leukemia (AML) xenografts compared to decitabine alone [ 39 ]. TRC105 enhanced the inhibitory effect of sunitinib on VEGF-VEGFR2-Akt-Creb signaling, indicating a molecular collaboration between TRC105 and Sunitinib [ 40 ].…”

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

“…The use of epigenetic drugs with other drugs such as etoposide, doxorubicin and bortezomib improves therapeutic potency in assays with various cancer cell lines [ 26 ], and Belinky et al demonstrated improved efficacy in lung cancer following treatment of mice with a combination of decitabine and PBA [ 27 ]. Likewise, the combined use of decitabine with an anti-CD105 therapeutic antibody caused a more durable anti-leukemic effect in a xenograft model of acute myeloid leukemia [ 28 ], and Venetoclax, i.e., an oral inhibitor of BCL-2 combined with decitabine or azacitidine, achieved nearly 70% complete remission in treatment-naive, elderly patients with acute myeloid leukemia [ 29 ].…”