Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma

Wahaib, Kristy; Beggs, Ashton E.; Campbell, H; Kodali, Leela; Ford, Patrick D.

doi:10.2146/ajhp150487

Cited by 25 publications

(13 citation statements)

References 14 publications

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“…Epigenetic abnormalities are abundantly present in multiple myeloma (MM) and have increasingly demonstrated critical roles for tumor development and resistance to therapy [ 3 – 7 ]. Therapeutic strategies that target epigenetic modifiers have recently gained momentum in many cancers including recent FDA approval for the pan-HDAC inhibitor panobinostat (PAN) in MM [ 8 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

2018

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Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation. Pre-treatment with EZH2 inhibitors greatly enhanced the sensitivity of HMCLs to the pan-HDAC inhibitor panobinostat in nearly all cases regardless of single agent EZH2 inhibitor sensitivity. Transcriptomic profiling revealed large-scale transcriptomic alteration by EZH2 inhibition highly enriched for cancer-related pathways. Combination treatment greatly increased the scale of gene expression change with a large portion of differentially expressed genes being unique to the combination. Transcriptomic analysis demonstrated that combination treatment further perturbed oncogenic pathways and signaling nodes consistent with an antiproliferative/pro-apoptotic state. We conclude that combined inhibition of HDAC and EZH2 inhibitors is a promising therapeutic strategy to broadly target the epigenetic landscape of aggressive MM.

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Section: Introductionmentioning

confidence: 99%

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

2018

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“…According to manufacturer's labeling, panobinostat is orally administered in a schedule of 20 mg starting dose once every other day for 3 doses each week during weeks 1 and 2 of a 21day cycle for up to 8 cycles [67]. e total duration of therapy may continue up to 16 3-week cycles if the patient shows clinical benefit and manageable toxicity.…”

Section: Administration Schedulementioning

confidence: 99%

Efficacy of Panobinostat for the Treatment of Multiple Myeloma

Eleutherakis‐Papaiakovou

Kanellias

Kastritis

et al. 2020

Journal of Oncology

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Panobinostat represents a potent oral nonselective pan-histone deacetylase inhibitor (HDAC) with activity in myeloma patients. It has been approved by the FDA and EMA in combination with bortezomib and dexamethasone for the treatment of multiple myeloma, in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent. In order to further explore its clinical potential, it is evaluated in different combinations in relapsed/refractory and newly diagnosed multiple myeloma. This review focuses on available data about panobinostat’s pharmacology and its role in clinical practice. This review will reveal panobinostat’s efficacy as antimyeloma treatment, describing drug evolution from preclinical experimental administration to administration in phase III trials, which established its role in current clinical practice. Based on the latest data, we will present its mechanism of action, its efficacy, and most important issues regarding its toxicity profile. We will further try to shed light on its role in current and future therapeutic landscape of myeloma patients. Panobinostat retains its role in therapy of multiple myeloma because of its manageable toxicity profile and its efficacy, mainly in heavily pretreated multiple myeloma patients. These characteristics make it valuable also for novel regimens in combination with second-generation proteasome inhibitors, IMiDs, and monoclonal antibodies. Results of ongoing trials are expected to shed light on drug introduction in different therapeutic combinations or even at an earlier level of disease course.

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“…Combination therapy based on the second-generation HDACi vorinostat or entinostat yielded an increased complete remission rate as compared to historical controls ( 151 ). The second-generation pan-HDACi panobinostat modulates gene expression by inducing hyperacetylation of core histone proteins, H3 and H4, and was shown to exhibit antitumor activity against several hematologic tumors, both in vitro and in vivo ( 107 , 152 ). Even though potent and orally bioavailable, panobinostat yields modest result as a single agent in elderly patients with AML.…”

Section: The Advantage Of Epigenetic Therapiesmentioning

confidence: 99%

Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia

2018

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The importance of epigenetic dysregulation to acute myeloid leukemia (AML) pathophysiology has become increasingly apparent in recent years. Epigenetic regulators, including readers, writers, and erasers, are recurrently dysregulated by way of chromosomal translocations, somatic mutations, or genomic amplification in AML and many of these alterations are directly implicated in AML pathogenesis. Mutations in epigenetic regulators are often discovered in founder clones and persist after therapy, indicating that they may contribute to a premalignant state poised for the acquisition of cooperating mutations and frank malignancy. Apart from the proto-oncogenic impact of these mutations, the AML epigenome is also shaped by other epigenetic factors that are not mutated but co-opted by AML oncogenes, presenting with actionable vulnerabilities in this disease. Targeting the AML epigenome might also be important for eradicating AML leukemia stem cells, which can be critical for disease maintenance and resistance to therapy. In this review, we describe the importance of epigenetic regulators in AML. We also summarize evidence implicating specific epigenetic regulators in AML pathobiology and discuss emerging epigenome-based therapies for the treatment of AML in the clinic.

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Panobinostat: A histone deacetylase inhibitor for the treatment of relapsed or refractory multiple myeloma

Cited by 25 publications

References 14 publications

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

Efficacy of Panobinostat for the Treatment of Multiple Myeloma

Epigenetic Regulators in the Development, Maintenance, and Therapeutic Targeting of Acute Myeloid Leukemia

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