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PloS One 2017Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI...
Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.
Topics: Antineoplastic Agents; Apoptosis; Bcl-2-Like Protein 11; Benzimidazoles; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Gene Deletion; Histone Deacetylase Inhibitors; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; RNA Splicing
PubMed: 28301600
DOI: 10.1371/journal.pone.0174107 -
Investigational New Drugs Aug 2015SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer...
BACKGROUND
SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC.
METHODS
Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed.
RESULTS
Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %).
CONCLUSION
Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Disease-Free Survival; Histone Deacetylase Inhibitors; Humans; Kallikreins; Male; Middle Aged; Neoplastic Cells, Circulating; PTEN Phosphohydrolase; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Serine Endopeptidases; Trans-Activators; Transcriptional Regulator ERG
PubMed: 25983041
DOI: 10.1007/s10637-015-0252-4 -
International Immunopharmacology Jun 2024A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE)....
Induction of indoleamine 2,3-dioxygenase 1 expression in neurons of the central nervous system through inhibition of histone deacetylases blocks the progression of experimental autoimmune encephalomyelitis.
BACKGROUND
A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE.
METHODS
We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution. We proved the involvement of IDO1 and the AHR in SB939-mediated immunosuppression using Ido1 and Ahr mice.
RESULTS
Administration with SB939 halted EAE progression, which depended upon IDO1 expression in neurons of the central nervous system (CNS). Our in vitro and in vivo studies demonstrated that SB939 sustained the interleukin-6-induced acetylation of STAT3, resulting in the stable transcriptional activation of Ido1. The therapeutic effect of SB939 also required the AHR, which is expressed mainly in CD4 T cells and macrophages in CNS disease lesions. Finally, SB939 was shown to markedly reduce the proliferation of CD4 T cells in inflamed neuronal tissues but not in the spleen or draining lymph nodes.
CONCLUSIONS
Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4 T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Indoleamine-Pyrrole 2,3,-Dioxygenase; Histone Deacetylase Inhibitors; STAT3 Transcription Factor; Mice, Inbred C57BL; Neurons; Mice, Knockout; Mice; Receptors, Aryl Hydrocarbon; Female; Spinal Cord; Myelin-Oligodendrocyte Glycoprotein; Central Nervous System; Hydroxamic Acids; Disease Progression; Histone Deacetylases; Peptide Fragments; Basic Helix-Loop-Helix Transcription Factors; Interleukin-6
PubMed: 38759372
DOI: 10.1016/j.intimp.2024.112246 -
Annals of Oncology : Official Journal... May 2015A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate...
BACKGROUND
A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway.
PATIENTS AND METHODS
SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods.
RESULTS
Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity.
CONCLUSION
This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population.
CLINICAL TRIAL
NCT01112384.
Topics: Administration, Oral; Adult; Antineoplastic Agents; Benzimidazoles; Biomarkers, Tumor; Canada; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Early Termination of Clinical Trials; Female; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Sarcoma; Time Factors; Translocation, Genetic; Treatment Outcome; Young Adult
PubMed: 25632070
DOI: 10.1093/annonc/mdv033