Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies

DeAngelo, Daniel J.; Spencer, Andrew; Bhalla, Kapil N.; Prince, H. Miles; Fischer, Tamás; Kindler, Thomas; Giles, Frank; Scott, Jeffrey W.; Parker, Kathy P.; Liu, A.; Woo, Margaret M.; Atadja, Peter; Mishra, Kaushal; Ottmann, Oliver G.

doi:10.1038/leu.2013.38

Cited by 121 publications

(101 citation statements)

References 55 publications

(72 reference statements)

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“…As the reported side effects of long-term HDACi treatment in cancer patients have been demonstrated to be manageable 18,55 , and panobinostat treatment in multiple myeloma patients has been well tolerated with significant disease benefit 39 , this suggests that if the shortterm immunosuppression can be managed effectively, an HDACi-based therapy could be well tolerated in autoimmune disease patients. At the low doses anticipated in the treatment of autoimmune disease, potential B-cell-dependent immune suppression could be treated with treatment interruption or dose reduction.…”

Section: Discussionmentioning

confidence: 99%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

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Histone deacetylase inhibitors (HDACi) are approved for treating certain haematological malignancies, however, recent evidence also illustrates they are modulators of the immune system. In experimental models, HDACi are particularly potent against malignancies originating from the B-lymphocyte lineage. Here we examine the ability of this class of compounds to modify both protective and autoimmune antibody responses. In vitro, HDACi affect B-cell proliferation, survival and differentiation in an HDAC-class-dependent manner. Strikingly, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduces autoreactive plasma-cell numbers, autoantibodies and nephritis, while other immune parameters remain largely unaffected. Immunized control mice treated with panobinostat or the clinically approved HDACi vorinostat have significantly impaired primary antibody responses, but these treatments surprisingly spare circulating memory B cells. These studies indicate that panobinostat is a potential therapy for B-cell-driven autoimmune conditions and HDACi do not induce major long-term detrimental effects on B-cell memory.

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Section: Discussionmentioning

confidence: 99%

Manipulation of B-cell responses with histone deacetylase inhibitors

et al. 2015

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“…Several types of HDACI have been used to treat patients with MM in clinical trials, including vorinostat (SAHA) and panobinostat, however, the response is poor (11)(12)(13). The modest, yet encouraging, single-agent activity observed with HDAC inhibitors in heavily pretreated patients with MM has led to their evaluation in combination with other novel therapeutic agents (14)(15)(16)(17)(18). The clinical activity of HDAC inhibitors in combination with proteasome inhibitors, IMiDs and conventional cytotoxic agents has been demonstrated in heavily pretreated MM patients, supporting the continued evaluation of these regimens in this patient population (19).…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Wang

Zhang

2012

Molecular Medicine Reports

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Abstract. The aim of the present study was to investigate the synergistic effects of valproic acid (VPA) and arsenic trioxide (ATO) on the proliferation of RPMI8226 cells and the possible underlying mechanisms. Cell apoptosis was assessed by flow cytometry. The mRNA expression levels were analyzed by semi-quantitative polymerase chain reaction, and the protein expression levels were analyzed by western blotting. The histone acetylation and methylation states of the gene promoters were detected using a chromatin immunoprecipitation technique. The apoptotic rates of the RPMI8226 cells in the combined drug groups were significantly increased compared with those of the single drug groups (P<0.05). The mRNA and protein expression levels of Bcl-2 and the expression levels of HDAC1 mRNA and H3K9me2 protein decreased significantly in the combined groups compared with the single drug groups. The mRNA and protein expression levels of Bax, Caspase 8, Caspase 9 and LSD1, and the protein expression of acetylated H3 increased significantly in the combination groups compared with the single drug groups. Histone methylation and acetylation of the Bcl-2 and bax gene promoters were increased in the combination groups compared with the single drug groups. VPA and ATO had synergistic effects on the proliferation of RPMI8226 cells, which may have been associated with the decreased expression of Bcl-2 and the increased expression levels of Bcl-2-associated X protein, Caspase 8 and Caspase 9. Therefore, the expression levels of the Bcl-2 gene family may have been regulated by the levels of gene promoter methylation and acetylation. IntroductionMultiple myeloma (MM) is a plasma cell disorder, characterized by anemia, renal disease, lytic bone disease, and immune dysfunction. MM is one of the most common types of hematological malignancy in China (1). Although currently approved treatments for newly diagnosed MM, including high-dose chemotherapy followed by autologous transplantation, and novel drugs, including proteasome inhibitors and immunomodulatory agents (IMiDs), have led to increased survival rates, the majority of patients will eventually relapse and become refractory to treatment (2). Therefore, patients with relapsed or refractory MM have an unmet requirement for safe and efficacious novel therapies.Arsenic trioxide (ATO) has been suggested as an option for the treatment of relapsing or refractory MM. In vitro, ATO has been found to induced myeloma cell apoptosis, and monotherapy with ATO results in partial response rates between 0 and 17%, and minimal responses between 7 and 33%, resulting in mean overall response rates of 30% for treatment of myeloma (3-5).In order to improve the treatment response rates in patients with MM, ATO has been combined with other novel drugs, including proteasome inhibitors, IMiDs and dexamethsone, for the treatment of MM. The overall response rates in these combined regimens vary widely between 12 and 100% (6-8). It is necessary to identify novel combinations of ATO with other drugs, to offer nov...

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“…6C). In this combination, the levels of panobinostat used are clinically achievable and safe and have been demonstrated to induce in vivo histone acetylation in cells of patients with AML (24). Notably, cotreatment with panobinostat and JQ1 did not exert significantly greater þ hematopoietic progenitor cells (Fig.…”

Section: Jq1 Inhibits the Binding Of Brd4 And Rna Pol II And Attenuatmentioning

confidence: 99%

“…We next determined whether cotreatment with the potent pan-HDAC inhibitor such as panobinostat, known to induce in vitro and in vivo lysine acetylation of histones, would increase the dependency on BRD4-regulated progrowth and prosurvival gene expressions and thereby sensitize AML BPCs to JQ1-induced apoptosis (19,24). Figure 5A and Supplementary Fig.…”

Section: Jq1 Inhibits the Binding Of Brd4 And Rna Pol II And Attenuatmentioning

confidence: 99%

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

Fiskus

Sharma

et al. 2014

Molecular Cancer Therapeutics

169

170

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The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1cþ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34 þ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142-54. Ó2014 AACR.

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Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies

Cited by 121 publications

References 55 publications

Manipulation of B-cell responses with histone deacetylase inhibitors

Manipulation of B-cell responses with histone deacetylase inhibitors

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells

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