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Leukemia & Lymphoma Jul 2019Although ruxolitinib improves symptoms and splenomegaly in patients with advanced myelofibrosis, whether this agent is truly disease-modifying remains unclear. Histone...
Although ruxolitinib improves symptoms and splenomegaly in patients with advanced myelofibrosis, whether this agent is truly disease-modifying remains unclear. Histone deacetylase inhibitors (HDACi) downregulate JAK2 via interference with chaperone function. Pracinostat, a pan-HDACi, has modest single-agent activity in myelofibrosis. We conducted a single-institution, phase 2, investigator-initiated trial of ruxolitinib plus pracinostat (begun after 12 weeks of ruxolitinib) in 25 patients with myelofibrosis, of whom 20 received both agents. Sixteen (80%) patients had objective responses (all 'clinical improvement'). The rate of spleen response (by palpation) was 74%, and that of symptom response 80%. Most responses occurred prior to pracinostat initiation. Three patients experienced improvement in bone marrow fibrosis, and one a near-complete molecular response after two years on study treatment. All patients discontinued pracinostat and are currently off-study. Pracinostat interruptions and dose reductions were frequent, often due to worsening anemia. These findings do not support continued development of pracinostat in myelofibrosis.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Primary Myelofibrosis; Prognosis; Pyrazoles; Pyrimidines; Survival Rate
PubMed: 30632841
DOI: 10.1080/10428194.2018.1543876 -
Cancer Discovery Nov 2018, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration...
, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad deletion in mouse neuroendocrine cells cooperated with loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that loss results in reduced expression of tight junction and cell adhesion genes, including , across neuroendocrine tumor types, whereas suppression of promoted transformation in SCLC. and other adhesion genes exhibited reduced histone acetylation with inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of -deficient SCLC exhibited exceptional responses to Pracinostat Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy. Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in -deleted tumors. These data provide a rationale for selectively treating -mutant SCLC with HDAC inhibitors. .
Topics: Acetylation; Animals; CREB-Binding Protein; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lung Neoplasms; Mice; Mice, Knockout; Mutation; Retinoblastoma Protein; Small Cell Lung Carcinoma; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 30181244
DOI: 10.1158/2159-8290.CD-18-0385 -
Cancer Dec 2017Pracinostat is a potent histone deacetylase inhibitor with antitumor activity in both solid tumor and acute myeloid leukemia (AML) cell lines. Pracinostat is reported to... (Comparative Study)
Comparative Study
BACKGROUND
Pracinostat is a potent histone deacetylase inhibitor with antitumor activity in both solid tumor and acute myeloid leukemia (AML) cell lines. Pracinostat is reported to have modest clinical activity in patients with advanced solid tumors. Given the higher preclinical sensitivity of hematologic malignancies to pracinostat, the authors conducted a phase 1 study to assess the safety, maximum tolerated dose, recommended phase 2 dose, efficacy, pharmacokinetics, and pharmacodynamics of pracinostat in patients with advanced hematological malignancies.
METHODS
Pracinostat was administered orally 3 times a week for 3 weeks on a 28-day cycle. Patients were assigned to 7 dose levels using a 3 + 3 dose escalation design.
RESULTS
A total of 44 patients were enrolled, 25 of whom had AML and 14 of whom had myelodysplastic syndrome. The maximum tolerated dose was 120 mg and the recommended phase 2 dose was 60 mg. Two patients with AML achieved a response: 1 complete remission (CR) and 1 complete cytogenetic response. Despite a dose-dependent increase in the plasma concentration of pracinostat, a similar increase in histone acetylation was not observed. As an extension, 10 additional patients with myelodysplastic syndrome were enrolled to assess the safety and efficacy of pracinostat in combination with azacitidine. Six patients achieved a CR and 3 achieved a CR without platelet recovery with no added toxicity.
CONCLUSIONS
The results of the current study demonstrate that pracinostat is safe, with modest single-agent activity in patients with hematological malignancies. Cancer 2017;123:4851-9. © 2017 American Cancer Society.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Azacitidine; Benzimidazoles; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Myelodysplastic Syndromes; Neoplasm Invasiveness; Neoplasm Staging; Patient Safety; Risk Assessment; Sex Factors; Survival Analysis; Treatment Outcome
PubMed: 28841236
DOI: 10.1002/cncr.30949 -
Nature Genetics Jul 2017Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene...
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.
Topics: Alternative Splicing; Animals; Benzimidazoles; Cell Line, Tumor; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Death-Associated Protein Kinases; Epigenetic Repression; Exons; Female; Gene Expression Profiling; Gene Silencing; Histone Code; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Introns; Mice; Mice, Nude; RNA Interference; Recombinant Fusion Proteins; Terminal Repeat Sequences; Transcription Initiation Site; Vorinostat
PubMed: 28604729
DOI: 10.1038/ng.3889 -
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 -
Current Treatment Options in Oncology Mar 2017Approximately 40-45% of younger and 10-20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is... (Review)
Review
Approximately 40-45% of younger and 10-20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is particularly gloomy for patients with relapsed and/or refractory disease (cure rates no higher than 10%). Allogeneic hematopoietic stem cell transplantation (HSCT), the only realistic hope of cure for these patients, is an option for only a minority. In recent years, much has been learned about the genomic and epigenomic landscapes of AML, and the clonal architecture of both de novo and secondary AML has begun to be unraveled. These advances have paved the way for rational drug development as new "drugable" targets have emerged. Although no new drug has been approved for AML in over four decades, with the exception of gemtuzumab ozogamycin, which was subsequently withdrawn, there is progress on the horizon with the possible regulatory approval soon of agents such as CPX-351 and midostaurin, the Food and Drug Administration "breakthrough" designation granted to venetoclax, and promising agents such as the IDH inhibitors AG-221 and AG-120, the smoothened inhibitor glasdegib and the histone deacetylase inhibitor pracinostat. In our practice, we treat most patients with relapsed/refractory AML on clinical trials, taking into consideration their prior treatment history and response to the same. We utilize targeted sequencing of genes frequently mutated in AML to identify "actionable" mutations, e.g., in FLT3 or IDH1/2, and incorporate small-molecule inhibitors of these oncogenic kinases into our therapeutic regimens whenever possible. In the absence of actionable mutations, we rationally combine conventional agents with other novel therapies such as monoclonal antibodies and other targeted drugs. For fit patients up to the age of 65, we often use high-dose cytarabine-containing backbone regimens. For older or unfit patients, we prefer hypomethylating agent-based therapy. Finally, all patients with relapsed/refractory AML are evaluated for allogeneic HSCT.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Recurrence; Retreatment; Treatment Outcome
PubMed: 28286924
DOI: 10.1007/s11864-017-0456-2 -
Cancer May 2017The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine.
METHODS
A phase 2 randomized, placebo-controlled clinical trial of azacitidine and pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2-risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy.
RESULTS
Of 102 randomized patients, there were 51 in the pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%).
CONCLUSIONS
The combination of azacitidine with pracinostat did not improve outcomes in patients with higher-risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017;123:994-1002. © 2016 American Cancer Society.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Benzimidazoles; Biomarkers; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Treatment Outcome
PubMed: 28094841
DOI: 10.1002/cncr.30533 -
International Immunopharmacology Jan 2017Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti-fibrotic agents is urgently needed....
Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti-fibrotic agents is urgently needed. Although histone deacetylases (HDACs) have been reported to be involved in renal fibrosis, current HDAC inhibitors are unsatisfactory anti-fibrosis drugs. Therefore, more potentially relevant anti-renal fibrosis HDAC inhibitors are needed. We initially found that non-cytotoxic concentrations of SB939 (pracinostat) had strong anti-fibrotic activity, drastically decreasing TGF-β1-induced alpha smooth muscle actin (α-SMA) expression in the NRK renal fibroblast cell line. Similar anti-fibrotic activity of SB939 on epithelial-to-mesenchymal transition (EMT) was confirmed using the HK-2 human renal proximal tubular epithelial cell line. SB939 inhibited Smad-independent TGF-β signaling involving the MAPK and PI3K/AKT pathways. To evaluate in vivo anti-fibrotic activity, we administered SB939 in a unilateral ureteric obstruction (UUO) model. SB939 treatment markedly inhibited the accumulation of α-SMA and tissue injury. Inflammatory and pro-fibrotic cytokines in the obstructed kidney were also significantly decreased by SB939 treatment. Our results suggest that SB939 might be a promising therapeutic drug for preventing renal fibrosis.
Topics: Animals; Anti-Inflammatory Agents; Benzimidazoles; Cell Differentiation; Cell Line; Disease Models, Animal; Fibrosis; Histone Deacetylase Inhibitors; Humans; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Myofibroblasts; Rats; Signal Transduction; Transforming Growth Factor beta; Ureteral Obstruction
PubMed: 27855304
DOI: 10.1016/j.intimp.2016.11.008 -
Molecular Cancer Therapeutics Jul 2016Improved treatment strategies are required for bladder cancer due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current...
Improved treatment strategies are required for bladder cancer due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current therapies. Histone deacetylase inhibitors (HDACi), approved as single agents for specific lymphomas, have shown promising preclinical results in solid tumors but could benefit from identification of biomarkers for response. Loss of activating transcription factor 3 (ATF3) expression is a feature of bladder tumor progression and correlates with poor survival. We investigated the utility of measuring ATF3 expression as a marker of response to the HDACi pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated the expression of ATF3, correlating with significant alteration in proliferative, migratory, and anchorage-dependent growth capacities. Pracinostat also induced growth arrest at the G0-G1 cell-cycle phase, coincident with the activation of tumor suppressor genes. In mouse xenograft bladder cancer models, pracinostat treatment significantly reduced tumor volumes compared with controls, accompanied by reexpression of ATF3 in nonproliferating cells from early to late stage of therapy and in parallel induced antiangiogenesis and apoptosis. Importantly, cells in which ATF3 expression was depleted were less sensitive to pracinostat treatment in vitro, exhibiting significantly higher proliferative and migratory properties. In vivo, control xenograft tumors were significantly more responsive to treatment than ATF3 knockdown xenografts. Thus, reactivation of ATF3 is an important factor in determining sensitivity to pracinostat treatment, both in vitro and in vivo, and could serve as a potential biomarker of response and provide a rationale for therapeutic utility in HDACi-mediated treatments for bladder cancer. Mol Cancer Ther; 15(7); 1726-39. ©2016 AACR.
Topics: Activating Transcription Factor 3; Animals; Antineoplastic Agents; Apoptosis; Benzimidazoles; Biomarkers; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Survival; Disease Models, Animal; Female; Gene Expression Regulation; Histone Deacetylase Inhibitors; Humans; Mice; Neoplastic Stem Cells; Transcriptional Activation; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays
PubMed: 27196751
DOI: 10.1158/1535-7163.MCT-15-0890 -
Pharmaceutical Biology Sep 2016Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown... (Review)
Review
Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown encouraging results in haematological malignancies, but the poor pharmacokinetic of these inhibitors leads to insufficient tumour concentration limiting their application against solid malignancies. Objective This article deals with novel HDAC inhibitor pracinostat (SB939) and delineates its therapeutic role in solid and haematological malignancies. The article provides rigorous details about the underlying molecular mechanisms modulated by pracinostat to exert cytotoxic effect. The article further highlights the doublet therapy that may be used to tackle monotonous cancer chemoresistance. Methods Both old and the latest literature on pracinostat was retrieved from diverse sources, such as PubMed, Science Direct, Springer Link, general Google search using both pracinostat and SB939 keywords in various ways: after thorough evaluation the topic which can fulfil the current gap was chosen. Results Pracinostat shows potent anticancer activity against both solid and haematological malignancies compared to the FDA-approved drug vorinostat. This marvellous inhibitor has better physicochemical, pharmaceutical and pharmacokinetic properties than the defined inhibitor vorinostat. Pracinostat has >100-fold more affinity towards HDACs compared to other zinc-dependent metalloenzymes and shows maximum efficacy when used in doublet therapy. Conclusion Pracinostat shows potent anticancer activity even against therapeutically challenging cancers when used in doublet therapy. However, the triplet combination studies of the defined inhibitor that may prove even more beneficial are still undone, emphasizing the desperate need of further research in the defined gap.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Neoplasms; Treatment Outcome
PubMed: 26853619
DOI: 10.3109/13880209.2015.1135966