Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi

Suraweera, Amila; O’Byrne, Kenneth J.; Richard, Derek J.

doi:10.3389/fonc.2018.00092

Cited by 551 publications

(458 citation statements)

References 146 publications

(147 reference statements)

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“…In the current study, approximately 19% of patients (per total cycle) had grade 1 to 2 QTc prolongation. 4 Conversely, the results of the current study demonstrate clear evidence of CXD101 activity in a range of lymphomas. 5 However, given the heterogenous nature of the patients, the interpatient dose variability, and the relatively small number of patients in the current study, we believe it is too early to specifically address whether the toxicity profile is superior to those of other less selective HDACis.…”

Section: Discussioncontrasting

confidence: 59%

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A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer

Eyre

Collins

Gupta

et al. 2018

Cancer

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BACKGROUND: In the current study, the authors sought to determine the maximum tolerated dose (MTD) of the novel class 1 selective histone deacetylase inhibitor CXD101 in a dose escalation study in patients with advanced solid tumors or recurrent/refractory lymphoma. METHODS: The authors escalated the dose of CXD101 from 1 mg twice daily orally for 5 days in a 21-day cycle (3+3 design). RESULTS: A total of 39 patients were enrolled, 36 of whom received CXD101. Of the 30 patients in the escalation cohort, 29 were evaluable for determination of the dose-limiting toxicity (DLT). DLTs were noted at doses of 16 mg twice daily (1 of 6 patients), 20 mg twice daily (1 of 6 patients), and 24/25 mg twice daily (2 of 5 patients, both of whom developed neutropenic fever). The MTD was 20 mg twice daily, which achieved maximal plasma concentrations (±standard deviation) of 231 ± 76 nM to 342 ± 126 nM, which was within the biologically active range. Six patients received 20 mg twice daily in an expansion cohort. The most frequent adverse events were fatigue, nausea, and reversible cytopenia. Key grade 3 to 4 adverse events (according to Common Terminology Criteria for Adverse Events criteria [version 4.03]) included thrombocytopenia (11%), neutropenia (17%), and neutropenic fever (2%) across the 133 CXD101 cycles given. The toxicity profile was similar to that of licensing studies with other histone deacetylase inhibitors. In 22 evaluable patients receiving a dose of ≥16 mg twice daily (17 of whom had lymphoma and 5 of whom had solid tumors), 3 partial responses (2 in patients with classic Hodgkin lymphoma after allogenic stem cell transplantation and 1 in a patient with angioimmunoblastic T-cell lymphoma) and 1 complete response (in a patient with follicular lymphoma) were noted (overall response rate of 18%) in addition to 9 patients who achieved durable stable disease. Responses were noted predominantly among patients with lymphoma (tumor reduction noted in 63% of patients on standard computed tomography). CONCLUSIONS: The MTD in the current study was found to be 20 mg twice daily. Encouraging and durable activity was observed in patients with Hodgkin lymphoma, T-cell lymphoma, and follicular lymphoma. Cancer 2019;125:99-108.

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Section: Discussioncontrasting

confidence: 59%

“…High HDAC expression is associated with poorer prognosis in, for example, patients with myeloma. 4 2 HDACis hyperacetylate nucleosomal histones, which tighten chromatin coiling with resultant silencing of gene expression, and are implicated in cell survival regulation, proliferation, differentiation, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer

Eyre

Collins

Gupta

et al. 2018

Cancer

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“…Although specifically treatment with NSC3852 suggested a potential for therapeutic applications in pediatric AML, future studies are required to further investigate the molecular mechanisms underlying these effects by transcriptomic and epigenomic analysis. In addition, more insights into toxicity, both hematological, including thrombocytopenia and anemia, and nonhematological, are needed in order to move forward to clinical studies …”

Section: Discussionmentioning

confidence: 99%

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia

Wiggers

Govers

Lelieveld

et al. 2019

Pediatric Blood & Cancer

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Background Acute myeloid leukemia (AML) is a heterogeneous disease regarding morphology, immunophenotyping, genetic abnormalities, and clinical behavior. The overall survival rate of pediatric AML is 60% to 70%, and has not significantly improved over the past two decades. Children with Down syndrome (DS) are at risk of developing acute megakaryoblastic leukemia (AMKL), which can be preceded by a transient myeloproliferative disorder during the neonatal period. Intensification of current treatment protocols is not feasible due to already high treatment‐related morbidity and mortality. Instead, more targeted therapies with less severe side effects are highly needed. Procedure To identify potential novel therapeutic targets for myeloid disorders in children, including DS‐AMKL and non‐DS‐AML, we performed an unbiased compound screen of 80 small molecules targeting epigenetic regulators in three pediatric AML cell lines that are representative for different subtypes of pediatric AML. Three candidate compounds were validated and further evaluated in normal myeloid precursor cells during neutrophil differentiation and in (pre‐)leukemic pediatric patient cells. Results Candidate drugs LMK235, NSC3852, and bromosporine were effective in all tested pediatric AML cell lines with antiproliferative, proapoptotic, and differentiation effects. Out of these three compounds, the pan‐histone deacetylase inhibitor NSC3852 specifically induced growth arrest and apoptosis in pediatric AML cells, without disrupting normal neutrophil differentiation. Conclusion NSC3852 is a potential candidate drug for further preclinical testing in pediatric AML and DS‐AMKL.

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“…Inhibition of HDAC1 and HDAC2 resulted in antitumor activity in urothelial carcinoma in vitro, whereas elevated HDAC1 is linked with poor prognosis in patients with urothelial carcinoma . HDAC inhibitors have demonstrated promise in clinical trials across a range of tumor types, and several have been approved by the US Food and Drug Administration, including vorinostat for patients with cutaneous T‐cell lymphoma, romidepsin for patients with cutaneous T‐cell lymphoma and peripheral T‐cell lymphoma, belinostat for patients with peripheral T‐cell lymphoma, and panobinostat for patients with multiple myeloma …”

Section: Introductionmentioning

confidence: 99%

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

Grivas

Mortazavi

Picus

et al. 2018

Cancer

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Background The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [ CREBBP ] and/or E1A binding protein p300 [ EP300 ] histone acetyltransferase genes in a single‐arm, open‐label phase 2 study. Methods Eligible patients with platinum‐treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28‐day cycles in a 3‐stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate. Results Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent‐to‐treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose‐normalized maximum serum concentration [C max ] after TIW dosing of 0.2 ng/mL/mg). Conclusions To the authors’ knowledge, the current study represents the first clinical trial using genomic‐based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.

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Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi

Cited by 551 publications

References 146 publications

A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer

A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer

Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

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