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Annals of Hematology Jun 2020Ruxolitinib is a targeted drug to treat myelofibrosis (MF). Ruxolitinib has significant advantages in spleen reduction and increasing 5-year overall survival (OS), and... (Review)
Review
Ruxolitinib is a targeted drug to treat myelofibrosis (MF). Ruxolitinib has significant advantages in spleen reduction and increasing 5-year overall survival (OS), and ruxolitinib-based combinations might provide more benefits than ruxolitinib monotherapy. In this review, we focus on the data of ruxolitinib-based combinations therapies and treatment-related adverse events (AEs) and safety. We analyzed and summarized the data of ruxolitinib-based combinations. Ruxolitinib combined with prednisone + thalidomide + danazol (TPD), panobinostat, pracinostat, azacytidine, or hydroxyurea has well reduced spleen. Ruxolitinib combined with danazol or TPD had well therapies in improvement of hemoglobin (Hgb) and platelets (PLT). Most ruxolitinib-based combinations therapies showed a superior benefit on reduced treatment-related AEs than ruxolitinib monotherapy. Treatment-related AEs and dose modification affect the safety and tolerability of ruxolitinib-based combinations. Genetic testing before treatment is recommended. To provide better clinical guidance, comparisons of these randomized controlled trials with the trials of ruxolitinib alone are necessary. This review suggests that the clinical application of ruxolitinib-based combinations is worth waiting for.
Topics: Clinical Trials as Topic; Drug Therapy, Combination; Humans; Immunologic Factors; Nitriles; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 32333155
DOI: 10.1007/s00277-020-04028-z -
Biomedicines Jan 2020Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and... (Review)
Review
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
PubMed: 32019149
DOI: 10.3390/biomedicines8020022 -
Cancers Nov 2019Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid... (Review)
Review
Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.
PubMed: 31739588
DOI: 10.3390/cancers11111794 -
Journal of Cell Science Oct 2019Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small...
Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβ-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene () in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.
Topics: Cell Line; Down-Regulation; Fibroblasts; Histone Deacetylases; Humans; Lung; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Promoter Regions, Genetic; Pulmonary Fibrosis; Transforming Growth Factor beta
PubMed: 31527052
DOI: 10.1242/jcs.233486 -
British Journal of Haematology Feb 2020Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and...
A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy.
Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.
Topics: Aged; Aged, 80 and over; Benzimidazoles; Bone Marrow; Drug Therapy, Combination; Female; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Myelodysplastic Syndromes
PubMed: 31468521
DOI: 10.1111/bjh.16173 -
Asian Pacific Journal of Cancer... Jun 2019Primary Myelofibrosis is a BCR-ABL negative myeloproliferative neoplasm with a variety of hematological presentations, including thrombosis, bleeding diathesis and... (Review)
Review
Primary Myelofibrosis is a BCR-ABL negative myeloproliferative neoplasm with a variety of hematological presentations, including thrombosis, bleeding diathesis and marrow fibrosis. It is estimated to have an incidence of 1.5 per 100,000 people each year. Although JAK2 or MPL mutations are seen in PMF, several other mutations have recently been documented, including mutations in CALR, epigenetic regulators like TET, ASXL1, and 13q deletions. The identification of these mutations has improved the ability to develop novel treatment options. These include JAK inhibitors like ruxolitinib, heat shock protein-90 inhibitors like ganetespib, histone deacetylase inhibitors including panobinostat, pracinostat, vorinostat and givinostat, hypomethylating agents like decitabine, hedgehog inhibitors like glasdegib, PI3K, AKT and mTOR inhibitors like everolimus as well as telomerase inhibitors like imtelstat. Research on novel therapeutic options is being actively pursued in order to expand treatment options for primary myelofibrosis however currently, there is no curative therapy other than allogenic hematopoietic stem cell transplantation (ASCT) which is possible in select patients.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Humans; Mutation; Primary Myelofibrosis; Prognosis; Protein Kinase Inhibitors
PubMed: 31244289
DOI: 10.31557/APJCP.2019.20.6.1691 -
International Journal of Molecular... Mar 2019Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical...
Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic library was screened against human neural progenitor cells (HNPCs) and WS1 human skin fibroblast cells using Cell-to-Ct assay kit to identify the small compounds capable of modulating the expression. In addition to two well-known hydroxamic acid-based histone deacetylase inhibitors (hb-HDACis), SAHA and TSA, several structurally similar HDAC inhibitors including SB-939, PCI-24781 and JNJ-26481585 with even higher impact on expression, were discovered in this study. Furthermore, by using well-developed immunohistochemistry assays, the selected compounds were also proved to have neurogenic potential improving the neurite outgrowth in HNPCs-derived neurons. In conclusion, we proved the neurogenic potential of several hb-HDACis, alongside their ability to enhance expression, which by modulating the neurogenesis and/or compensating for neuronal loss, could be propitious for treatment of neurological disorders.
Topics: Benzimidazoles; Benzofurans; Brain-Derived Neurotrophic Factor; Cells, Cultured; HEK293 Cells; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Neural Stem Cells; Neuronal Outgrowth
PubMed: 30841499
DOI: 10.3390/ijms20051109 -
Blood Advances Feb 2019Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity...
Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Benzimidazoles; Female; Humans; Leukemia, Myeloid, Acute; Male; Survival Analysis; Treatment Outcome
PubMed: 30760466
DOI: 10.1182/bloodadvances.2018027409 -
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