Responses to romidepsin in patients with cutaneous T-cell lymphoma (CTCL) with tumors and/or folliculotropic involvement.
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8575 Background: CTCL is a heterogeneous group of non-Hodgkin lymphomas that arises in the skin (patches, plaques, tumors, and/or erythroderma) but can involve the lymph, blood, and/or viscera. Additionally, patients with cutaneous tumors or folliculotropic involvement typically have poor prognoses. Romidepsin is a histone deacetylase inhibitor approved by the US FDA for the treatment of patients with CTCL who have received ≥ 1 prior systemic therapy. Durable responses (objective response rate [ORR; complete [CR] + partial responses] of 34% and median duration of response of 15 mo) and tolerability with extended dosing have been reported. To examine responses to romidepsin in these less favorable prognostic subsets, patients with tumors or folliculotropic involvement in the pivotal study of romidepsin for the treatment of CTCL were analyzed. Methods: Patients with CTCL (N = 96) who had ≥ 1 prior systemic therapy received romidepsin 14 mg/m2on days 1, 8, and 15 every 28 days. Responses were determined by a rigorous composite endpoint that included changes in the skin, blood, and lymph. Patients with cutaneous tumors or folliculotropic involvement were identified by reviewing diagnosis and histology reports. Results: Of 96 patients with CTCL, 20 had tumors, and 10 had folliculotropic involvement (2 had both). All but 2 patients with tumors and 1 with folliculotropic involvement achieved ≥ stable disease (SD) with romidepsin (Table). Time to response and DOR ranged from 0.9-4.7 mo and 1.4-18.7+ mo, respectively, for patients with tumors and 1.0-8.3 mo and 2.1-5.0+ mo for patients with folliculotropic involvement. Discontinuation due to an adverse event occurred in 1 patient with tumors (fatigue) and 0 with folliculotropic involvement. Conclusions: In the pivotal study of romidepsin for the treatment of CTCL, patients with cutaneous tumors or folliculotropic involvement commonly responded to therapy. Additionally, despite rapid onset of response, patients with tumors rarely discontinued romidepsin due to adverse events, with the longest duration of response ongoing at 18.7 mo. Clinical trial information: NCT00106431. Best response, n (%) Tumors (n = 20) Folliculotropic involvement (n = 10) ORR 9 (45) 6 (60) CR 2 (10) 1 (10) SD 9 (45) 3 (30)Keywords:
Romidepsin
Cutaneous T-cell lymphoma
Tolerability
Vorinostat
Histone deacetylase (HDAC) inhibitors such as vorinostat (suberoylanilide hydroxamic acid), valproic acid, romidepsin (FK-228), and LBH589 comprise a relatively new class of potent anticancer agents. This study provides evidence for the potential of vorinostat to cause acquisition of multidrug resistance protein-independent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (two-fold to three-fold), is nonreversible, and correlates with the loss of responses typically seen with HDAC inhibitors, that is the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-dependent and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (valproic acid) HDAC inhibitors but not to the benzamide-class (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The acquired HDAC inhibitor resistance described hereis not a result of altered HDAC and histone acetyltransferase activities and differs from that previously reported for romidepsin.
Romidepsin
Vorinostat
Depsipeptide
Histone deacetylase inhibitor
Valproic Acid
Hydroxamic acid
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Romidepsin
Vorinostat
Cutaneous T-cell lymphoma
Bexarotene
Brentuximab vedotin
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While several systemic therapies are approved for cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma of skin-homing T cells that may involve lymph nodes and peripheral blood in advanced stages, relapses are common. Mutational analysis of CTCL cells has revealed frequent amplification of the MYC oncogene, and bromodomain and extraterminal (BET) protein inhibitors have been shown to repress MYC expression in various malignancies. Towards a potential novel therapy, we thus sought to examine the effect of BET inhibition on CTCL cells in vitro. Each of the four tested BET inhibitors (JQ1, ABBV-075, I-BET762, CPI-0610) consistently induced dose-dependent decreases in viability of isolated patient-derived CTCL cells and established CTCL cell lines (MyLa, Sez4, HH, Hut78). This effect was synergistically potentiated by combination of BET inhibition with BCL2 inhibition (e.g. venetoclax) or histone deacetylase (HDAC) inhibition (e.g. vorinostat or romidepsin). There was also a marked increase in caspase 3/7 activation when JQ1 was combined with either vorinostat or romidepsin, confirming that the observed synergies are due in major part to induction of apoptosis. Furthermore, MYC and BCL2 expression were each synergistically repressed when CTCL cells were treated with JQ1 plus HDAC inhibitors, suggesting cooperative activities at the level of epigenetic regulation. Taken together, these data indicate that targeting BET proteins in CTCL represents a promising novel therapeutic strategy that may be substantially potentiated by combination with BCL2 or HDAC inhibition.
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Vorinostat
Cutaneous T-cell lymphoma
Venetoclax
BET inhibitor
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Progress in clinical trial of histone deacetylase (HDAC) inhibitors for non-small cell lung cancers*
Histone deacetylase (HDAC) inhibitors, which represent a structurally diverse group of molecules, have emerged as a novel therapeutic class of molecules with significant anticancer potential. Vorinostat and romidepsin, known as the first generation of HDAC inhibitors, were approved in the United States for the treatment of T-cell lymphomas. Preliminary activity of HDAC inhibitors has also been observed in non-small cell lung cancer (NSCLC) in combination with the existing treatment regimens, of which is the focus of the current review.
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Vorinostat
Histone deacetylase inhibitor
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<div>Abstract<p>Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and vorinostat is now an approved drug for the treatment of cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of hematologic malignancies, it is possible that different drugs may have different mechanistic, biological, and therapeutic activities. When comparing an HDACi belonging to the hydroxamic acid class of compounds (vorinostat) with a cyclic tetrapeptide (romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the Eμ-myc mouse model of B-cell lymphoma, we showed previously that overexpression of the prosurvival proteins Bcl-2 and Bcl-X<sub>L</sub> inhibited the apoptotic and therapeutic activities of the vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the hydroxamic acid oxamflatin with romidepsin. Like vorinostat, oxamflatin was unable to kill lymphomas overexpressing Bcl-2 and Bcl-X<sub>L</sub>, indicating that these proteins can generally protect cells against this class of HDACi. In contrast, romidepsin was able to induce apoptosis in lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these lymphomas. However, romidepsin was inactive when Bcl-X<sub>L</sub> was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and biological activities. [Mol Cancer Ther 2008;7(5):1066–79]</p></div>
Romidepsin
Vorinostat
Histone deacetylase inhibitor
Depsipeptide
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Cutaneous T-cell lymphoma
Vorinostat
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Citations (28)
Background: Histone deacetylase inhibitors (HDACis), such as vorinostat and romidepsin, are promising agents for various T-cell lymphomas, including cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia. Despite the promising anti-lymphoma activity of HDACis, resistance remains a significant clinical problem. Therefore, novel therapeutic strategies to overcome HDACi resistance are required. In this study, we generated HDACi-resistant CTCL cell lines and investigated the mechanisms of HDACi resistance. Aims: The aim of the study was to identify the mechanism of resistance to HDACis in CTCLs and to explore new therapeutic targets. Methods: CTCL cell lines My-La, MJ, and Hut78 were used in the study. Vorinostat-resistant cell lines MyLa resistant, HUT78 resistant, and MJ resistant were prepared by repeatedly exposing cells to increasing concentrations of vorinostat. To maintain drug resistance, cells were continuously cultured in a medium containing 2.5 μM vorinostat. Following this, we conducted a comprehensive gene expression analysis using a microarray platform to investigate deregulated genes in the resistant cell lines. Results: CTCL cell lines resistant to vorinostat were also resistant to romidepsin, suggesting that vorinostat-resistant cell lines were cross-resistant to other HDACis. Next, we selected genes whose expression was upregulated more than two-fold in the three resistant cell lines and performed pathway analysis. Pathway analysis revealed that upregulated genes were significantly enriched in cytokine-mediated signaling pathways. Among the upregulated genes, we focused on IL6ST/gp130, which forms a heterogeneous complex with IL6 and IL6 receptor and activates the JAK/STAT pathway. Further, flow cytometric analysis revealed that surface gp130 expression was significantly upregulated in resistant cell lines. Moreover, resistant cell lines showed an increased sensitivity to a gp130 inhibitor (SC144), and gp130 activation could activate the JAK/STAT pathway. Accordingly, we examined the expression level of the activated form of STAT3, that is p-STAT3, and found that p-STAT3 was significantly upregulated in resistant cell lines. To investigate whether p-STAT3 upregulation is involved in the acquisition of vorinostat resistance, we performed STAT3 knockdown using an siRNA. We confirmed that STAT3 knockdown significantly decreased the survival of resistant cell lines. Moreover, resistant cell lines showed increased sensitivity to the STAT3-selective inhibitor, C188-9. We also examined the expression level of p-STAT5; however, it was downregulated in resistant cell lines, which was opposite to that of p-STAT3. Finally, we examined gp130 and p-STAT3 protein expression in CTCL skin samples, which were obtained from the same patients before and after vorinostat treatment. We found that gp130 and p-STAT3 expression significantly increased in the specimens at the time of relapse after vorinostat treatment. Summary/Conclusion: Activation of STAT3 in HDACi-resistant CTCL cells was enhanced via gp130, which contributed to their resistance. These results suggested that STAT3 could be a new therapeutic target in HDACi-resistant CTCL, and gp130/STAT3 inhibition could be an important therapeutic strategy.
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Histone deacetylase inhibitor
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Abstract Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade, inhibition of HDACs came out as a target for specific epigenetic changes associated with cancer and other diseases. Until now, more than 20 HDAC inhibitors (HDACIs) have entered clinical studies, and some of them (e.g., vorinostat, romidepsin) have been approved for the treatment of cutaneous T‐cell lymphoma. This review provides an overview of current knowledge, progress, and molecular mechanisms of HDACIs, covering a period from 2011 until 2015.
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<div>Abstract<p>Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and vorinostat is now an approved drug for the treatment of cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of hematologic malignancies, it is possible that different drugs may have different mechanistic, biological, and therapeutic activities. When comparing an HDACi belonging to the hydroxamic acid class of compounds (vorinostat) with a cyclic tetrapeptide (romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the Eμ-myc mouse model of B-cell lymphoma, we showed previously that overexpression of the prosurvival proteins Bcl-2 and Bcl-X<sub>L</sub> inhibited the apoptotic and therapeutic activities of the vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the hydroxamic acid oxamflatin with romidepsin. Like vorinostat, oxamflatin was unable to kill lymphomas overexpressing Bcl-2 and Bcl-X<sub>L</sub>, indicating that these proteins can generally protect cells against this class of HDACi. In contrast, romidepsin was able to induce apoptosis in lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these lymphomas. However, romidepsin was inactive when Bcl-X<sub>L</sub> was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and biological activities. [Mol Cancer Ther 2008;7(5):1066–79]</p></div>
Romidepsin
Vorinostat
Histone deacetylase inhibitor
Depsipeptide
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Abstract Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and vorinostat is now an approved drug for the treatment of cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of hematologic malignancies, it is possible that different drugs may have different mechanistic, biological, and therapeutic activities. When comparing an HDACi belonging to the hydroxamic acid class of compounds (vorinostat) with a cyclic tetrapeptide (romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the Eμ-myc mouse model of B-cell lymphoma, we showed previously that overexpression of the prosurvival proteins Bcl-2 and Bcl-XL inhibited the apoptotic and therapeutic activities of the vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the hydroxamic acid oxamflatin with romidepsin. Like vorinostat, oxamflatin was unable to kill lymphomas overexpressing Bcl-2 and Bcl-XL, indicating that these proteins can generally protect cells against this class of HDACi. In contrast, romidepsin was able to induce apoptosis in lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these lymphomas. However, romidepsin was inactive when Bcl-XL was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and biological activities. [Mol Cancer Ther 2008;7(5):1066–79]
Romidepsin
Vorinostat
Histone deacetylase inhibitor
Depsipeptide
Cutaneous T-cell lymphoma
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Citations (67)