1.The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR.
Zhou L1, Chen S1, Zhang Y1, Kmieciak M1, Leng Y2, Li L2, Lin H1, Rizzo KA3, Dumur CI3, Ferreira-Gonzalez A3, Rahmani M1, Povirk L4, Chalasani S4, Berger AJ5, Dai Y1, Grant S6. Blood. 2016 Feb 5. pii: blood-2015-06-653717. [Epub ahead of print]
Two classes of novel agents i.e., NAE (NEDD8-activating enzyme) and HDAC (histone deacetylase) inhibitors have shown single-agent activity in AML/MDS. Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat co-administration synergistically induced AML cell apoptosis (~ 20% individually; 60-90% combined; CI values <1.0) with or without p53 deficiency or FLT3-ITD, while p53 shRNA knock-down or enforced FLT3-ITD expression significantly sensitized cells to the regimen (P < 0.05). MLN4924 blocked belinostat-induced anti-apoptotic gene expression through NF-κB inactivation. Each agent up-regulated Bim, and Bim knock-down significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual versus combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/down-regulation, co-treatment down-regulated multiple HR and NHEJ repair proteins, triggering robust DSBs, chromatin pulverization, and apoptosis.
2.An overview of investigational Histone deacetylase inhibitors (HDACis) for the treatment of non-Hodgkin's lymphoma.
Apuri S1, Sokol L1. Expert Opin Investig Drugs. 2016 Mar 25:1-10. [Epub ahead of print]
INTRODUCTION: Histone acetylation alters DNA transcription and protein expression. Aberrant acetylation is seen in tumor cells. Histone deacetylase inhibitors (HDACis) act by modifying gene expression and are the newest class of drugs shown to be promising in patients with several malignancies including relapsed and/or refractory lymphoma. Multiple HDACis are currently under various phases of clinical trials for the treatment of Non-Hodgkin's lymphoma (NHL). Areas Covered: This review discusses the mechanism of histone acetyl transferases (HAT's), histone deacetylases (HDAC's) and their role in B - and T-cell malignancies with a particular focus on the mechanism of action and clinical application of HDACis in NHL. Discussion includes: HDACi's like vorinostat, romidepsin, belinostat, panobinostat, entinostat and chidamide; pivotal clinical trials leading to the approval of HDACis in NHL; ongoing active clinical trials and combination therapies with novel agents.
3.Pharmacokinetics, metabolism, and excretion of (14)C-labeled belinostat in patients with recurrent or progressive malignancies.
Calvo E1, Reddy G2, Boni V1, García-Cañamaque L3, Song T2, Tjornelund J4, Choi MR5, Allen LF2. Invest New Drugs. 2016 Apr;34(2):193-201. doi: 10.1007/s10637-015-0321-8. Epub 2016 Jan 14.
Background Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (50-70 %), with renal excretion accounting for ~30-50 %. A Phase 1 human mass balance study was conducted to identify species-dependent variations in belinostat metabolism and elimination. Methods Patients received a single 30-min intravenous (IV) infusion of (14)C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography - tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m(2) on Days 1-5 every 21 days) was permitted.
4.Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: Peripheral T-cell lymphomas.
Zinzani PL1, Bonthapally V2, Huebner D3, Lutes R3, Chi A4, Pileri S5. Crit Rev Oncol Hematol. 2016 Mar;99:214-27. doi: 10.1016/j.critrevonc.2015.12.016. Epub 2016 Jan 3.
Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of patients developing relapsed/refractory disease. Prior to 2009, chemotherapies were the only options for relapsed/refractory PTCL, other than hematopoietic transplants. However, chemotherapy only improves survival by about 1 month compared with palliation. Four drugs are now approved in the US to treat relapsed/refractory PTCL: pralatrexate, romidepsin, belinostat, and brentuximab vedotin (for systemic anaplastic large cell lymphoma [sALCL]). Response rates with pralatrexate, romidepsin, and belinostat range from 25 to 54% in mixed relapsed/refractory PTCL populations, while 86% of sALCL patients respond to brentuximab vedotin. Here, we critically evaluate the evidence supporting the current drug treatment of relapsed/refractory PTCL, and look to the future to see how the treatment panorama may change with the advent of new targeted therapies, some of which (e.