Entinostat, a novel histone deacetylase inhibitor is active in B‐cell lymphoma and enhances the anti‐tumour activity of rituximab and chemotherapy agents

Abstract

Summary Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma-bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma.

Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma

“…That being said, further preclinical analyses are necessary to assess the tolerability and efficacy of RV in combination with clinically relevant HDACi. In fact, although AR-42 as a single agent in our trial (NCT 01798901) was well tolerated in 26 patients with hematopoietic diseases, including MM, it displayed a shorter half-life (4–56hrs, C max 0.3–1.2μM) compared to Entinostat (33). On the other hand, LBH has been recently approved for the treatment of MM and may result in the most valuable companion drug for RV therapy in relapse patients.…”

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

“…Although the underlying mechanisms are not clear, HDAC inhibitors are wildly used in combination with chemotherapeutic agents to enhance anticancer activity [46–49]. As a selective class I HDAC inhibitor, entinostat has shown promising efficacy in the treatment of B cell lymphomas [39,40,50]. Our previous studies also revealed that entinostat in combination with melphalan or bendamustine synergistically induced growth inhibition and apoptosis in MM cells [51,52].…”

“…In clinic testing, entinostat shows benefit in estrogen receptor-positive breast cancer [32], non-small cell lung cancer [33], melanoma [34], and some T cell lymphoma [35–38]. Its combination with chemotherapy demonstrates enhanced efficacy in B cell lymphoma [37,39–41]. In the current study, we have attempted to seek the combinatorial effects of cladribine and entinostat on cell proliferation and survival in MM cells, and explore the underlying mechanism that cladribine combined with entinostat serves as a novel therapeutic strategy against MM.…”

Combination of 177Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

“…The activity of 177 Lu‐lilotomab used was approximately 50% of the maximum tolerated dosage (MTD) and was chosen so that the therapeutic effect of the single treatment was suboptimal in order to be able to detect an increased effect of the combination with rituximab. The same thinking guided the choice of rituximab dosage which was chosen based on published data on similar animal models . Nine to ten mice were used per group.…”

“…The same thinking guided the choice of rituximab dosage which was chosen based on published data on similar animal models. 31,32 Nine to ten mice were used per group. Mice were administered with the first treatment on day 8; study day 0 was set at injection of tumour cells.…”