Treatment Of Cutaneous T-cell Lymphoma Research Articles

Identification and characterization of PKF118-310 as a KDM4A inhibitor

ABSTRACTEpigenetic modifications are functionally involved in gene expression regulation. In particular, histone posttranslational modifications play a crucial role in functional chromatin organization. Several drugs able to inhibit or stimulate some families of proteins involved in epigenetic histone regulation have been found, a number of which are FDA-approved for the treatment of cutaneous T-cell lymphoma or are in phase I/II/III clinical trials for solid tumors. Although some protein families, such as histone deacetylases and their inhibitors, are well characterized, our understanding of histone lysine demethylases is still incomplete. We describe the in silico, in vitro, and cell-based characterization of the compound PKF118-310, an antagonist of transcription factor 4 (TCF4)/β-catenin signaling, as inhibitor of KDM4A. PKF118-310 potential inhibitor activity was discovered via virtual screening on the crystal structure of KDM4A. A peptide-based histone trimethylation assay developed in-house confirmed its potent KDM4A inhibitor activity. Its protein target was identified by cellular thermal shift assay experiments. PKF118-310 anticancer activity was observed in both liquid and solid tumor cells, and shown to have a dose- and time-dependent effect. We demonstrate the previously unreported inhibitory action of PKF118-310 on KDM4A. Our findings open up the possibility of developing the first KDM4A-specific inhibitors and derivatives.

The Search for Potent, Small‐Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat

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.

Natural and Structure-based RXR Ligand Scaffolds and Their Functions.

Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. Through these liaisons RXR ligands ("rexinoids") either transcriptionally activate on their own the "permissive" subclass of heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) or synergize with partner ligands in the "non-permissive" subclass of heterodimers (RAR/RXR, VDR/RXR and TR/RXR). The nature and extent of the interaction of the ligand-receptor complexes with co-regulators, which is cell and context-dependent, results ultimately in transcriptional modulation of cognate gene networks. RXR modulators hold therapeutical potential for the treatment of cancer and other diseases related to nutrient acquisition and disposal, among them metabolic diseases. A rexinoid (bexarotene) has indeed reached the clinic for the treatment of cutaneous T-cell lymphoma. The modulation of RXR function by rexinoids acting as agonists, parcial agonists, inverse agonists or antagonists is encoded in the structure of the ligandreceptor complexes. A very large number of rexinoids with a wide structural diversity has been published. In addition to natural products and other ligands discovered by HTS or mere serendipity, most rexinoids have been rationally designed based on the structures of existing complexes with RXR determined by X-Ray or based on Molecular Modeling. Although the structural rationale for the modulation of the ligand-receptor complexes is reasonably well understood, it has not yet been possible to predict the correlation between ligand structure and physiological response, particularly in the case of heterodimer-selective rexinoids.

New Targeted Treatments for Cutaneous T-cell Lymphomas.

Cutaneous T-cell lymphomas (CTCLs) represent a group of rare and heterogeneous diseases that are very difficult to treat at advanced stages. The development of monoclonal antibodies is a new hope for the treatment of these diseases. Alemtuzumab (Campath) is a humanized IgG1 kappa monoclonal antibody specific for CD52, an antigen expressed by most T and B lymphocytes. Alemtuzumab may frequently induce long-term remissions in patients with Sezary syndrome but high-dose treatments lead to severe cytopenia, immune depletion, and opportunistic infections. This treatment is less efficient in mycosis fungoides (MF). Brentuximab vedotin is a chimeric anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E, a cytotoxic antitubulin agent. Brentuximab vedotin is a very interesting new treatment for advanced tumor MF, Sezary syndrome, and primary cutaneous CD30+ lymphoproliferative disorders. The main limiting adverse event is neurosensitive peripheral neuropathy. Mogamulizumab is a humanized anti-C-C chemokine receptor Type 4 monoclonal antibody with a defucosylated Fc region leading to increased antibody-dependent cellular cytotoxicity. Mogamulizumab is very efficient on aggressive peripheral T-cell lymphomas, particularly adult T-cell leukemia/lymphoma and CTCLs, especially on the blood component of tumor cells. The main limiting events are related to the concomitant depletion of regulatory T-cells. IPH4102 is a humanized monoclonal antibody that targets the immune receptor KIR3DL2/CD158k. Preclinical results with this antibody offer proofs of concept for the clinical development of IPH4102 to treat patients with advanced CTCL.

Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells.

Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here we show that trichostatin A, romidepsin, and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine, and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo. Importantly, these pro-apoptotic effects are mimicked by RASGRP1 siRNA or HSP90 inhibition and reversed by overexpression of constitutively active MEK1 or siRNA-mediated downregulation of BIM. Collectively, these observations not only identify a new HSP90 client protein, RASGRP1, but also delineate a complete signaling pathway from HSP90 acetylation through RASGRP1 and CRAF degradation to BIM upregulation that contributes to selective cytotoxicity of HDAC inhibitors in lymphoid malignancies.

Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma

Bexarotene is currently marketed for treatment of cutaneous T-cell lymphoma and there has been growing interest in its therapeutic effectiveness for other cancers. Neuroprotective effects of bexarotene have also been reported. In this study, a simple, sensitive and cost-efficient bioanalytical method for determination of bexarotene in rat plasma was developed and fully validated. The method utilises protein precipitation with acetonitrile and liquid-liquid extraction with n-hexane-ethyl acetate (10:1, v/v). An HPLC-UV system with a Waters Atlantis C18 column and a mobile phase of acetonitrile-ammonium acetate buffer (10mM, pH 4.1) at a ratio of 75:25 (v/v), flow rate 0.2mL/min was used. Chromatograms were observed by a UV detector with wavelength set to 259nm. Intra- and inter-day validations were performed and sample stability tests were conducted at various conditions. The applicability of the method was demonstrated by a pharmacokinetic study in rats. Intravenous bolus dose of 2.5mg/kg was administered to rats and samples were obtained at predetermined time points. As a result, pharmacokinetic parameters of AUCinf (4668±452hng/mL), C0 (6219±1068ng/mL) and t1/2 (1.15±0.02h) were obtained. In addition, the developed method was further applied to human and mouse plasma to assess the suitability of the method for samples from other species.

A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

Small molecule-based nanodrugs with nanoparticles (NPs) that are mainly composed of small molecules, have been considered as a promising candidate for a next-generation nanodrug, owing to their unique properties. Vorinostat (SAHA) is a canonical US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma. However, the lack of efficacy against solid tumors hinders its progress in clinical use. Herein, a novel nanodrug of SAHA was developed based on disulfide-linked prodrug SAHA-S-S-VE. SAHA-S-S-VE could self-assemble into 148 nm NPs by disulfide-induced mechanisms, which were validated by molecular dynamics simulations. Under reduced conditions, the redox-responsive behavior of SAHA-S-S-VE was investigated, and the HDAC inhibition results verified the efficient release of free SAHA. With a biocompatible d-a-tocopheryl polyethylene glycol succinate (TPGS) functionalization, the SAHA-S-S-VE/TPGS NPs exhibited low critical aggregation concentration of 4.5 μM and outstanding stability in vitro with drug-loading capacity of 24%. In vitro biological assessment indicated that SAHA-S-S-VE/TPGS NPs had significant anticancer activity against HepG2. Further in vivo evaluation demonstrated that the resulting NPs could be accumulated in the tumor region and inhibit the tumor growth effectively. This approach, which turned SAHA into a self-assembled redox-responsive nanodrug, provided a new channel for the use of HDAC inhibitor in solid tumor therapy.

Process Development of the Soft Histone Deacetylate Enzyme Inhibitor SHP-141: Acylation of Methyl Paraben and Suberyl Hydroxamic Acid Formation

SHP-141 (1) is a hydroxamic acid-based inhibitor of histone deacetylase enzymes which is under development for the treatment of cutaneous T-cell lymphoma. The original synthesis of 1 involved five synthetic steps beginning with suberic acid monomethyl ester. Final deprotection of the O-benzyl hydroxamate moiety using hydrogen and palladium catalyst mandated the use of metal scavengers to reduce palladium levels to within International Council for Harmonisation (ICH) guidance. Owing to the sensitivity of 1 toward self-condensation and the potential for N–O bond cleavage under hydrogenolytic conditions, we developed an alternative route to 1 which avoids Pd-mediated hydrogenation and prolonged metal scavenger treatment. This two-step process employs readily available suberic acid and methyl paraben and has successfully delivered multiple kilograms of 1 for clinical use. Importantly, crude 1 was stabilized for recrystallization in acetonitrile (ACN) solution by the addition of 0.1% citric acid and 4% water. ...

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN).

Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC50 profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.

Abstract 4727: ST7612AA1: focus on a drug candidate, front-runner of a new generation of HDAC inhibitors

Abstract After more than 20 years of research in the field of HDAC inhibitors, the oncological armamentarium has significantly enriched with new approved drugs. Currently, four drugs, Vorinostat (Zolinza; 2006), Romidepsin (Istodax; 2009) Belinostat (Beleodaq; 2014) and Panobinostat (Farydak; 2015) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and multiple myeloma, respectively. A fifth, Chidamide (Epidaza; 2015), has been recently approved by the China Food and Drug Administration for the treatment of PTCL. Beyond them, more than twenty are currently under pre-clinical and clinical investigation as single agent and in combination therapies against different cancers and in other several novel therapeutic indications. However, it is to emphasize a feature: among all these, no one, with the exception of the natural product Romidepsin, is a thiol derivative. After efforts lasted years, now we have selected ST7612AA1 - a new thiol-ω(γ-lactam amide) SAHA analogues, potential front-runner of a new generation of HDAC inhibitors, [1] highly competitive respect to other HDAC inhibitors drugs, orally administered with a negligible toxicity. ST7612AA1 displays low-nanomolar inhibitor activity on HDACs, being especially powerful on HDAC6 isoform, associated to a wide spectrum of antitumor activity, both in vitro and in vivo [2]; it can be industrially developed with a quick and easy synthetic process [3]. Moreover, it has also been investigated as an enhancer in antiretroviral therapy against HIV, aimed to eradicate the viral reservoirs [4]. All these results encouraged further enrichment experiments with ST7612AA1 as a drug candidate, which is currently in a phase of pre-clinical evaluation. The overall profile of ST7612AA1, including synthesis and a comprehensive pharmacological characterization, will be presented. [1] G. Giannini et al. J Med Chem. 2014, 57, 8358-8377 [2] L. Vesci et al. Oncotarget 2015, 6, 5735-48 [3] G. Battistuzzi, G. Giannini. Bioorg. Med. Chem .Lett. 2015, submitted [4] R. Badia Antiviral Research 2015, 123, 62-69 Citation Format: Giuseppe Giannini, Ferdinando Maria Milazzo, Gianfranco Battistuzzi, Loredana Vesci. ST7612AA1: focus on a drug candidate, front-runner of a new generation of HDAC inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4727.

Abstract 4728: Histone deacetylase inhibitors induce apoptosis in multiple tumor types through induction of ATF3

Abstract Histone deacetylase inhibitors (HDACi) are approved for the treatment of cutaneous T-Cell lymphoma (CTCL) and Multiple Myeloma. In colon cancer cells HDACi-induced apoptosis is linked to induction of a specific transcriptional response involving upregulation of the immediate-early (IE) response genes FOS, JUN, EGR1, EGR3 and ATF3. To determine if this transcriptional response underpins HDACi-induced apoptosis across multiple tumour types, including CTCL and MM, 50 cell lines derived from common solid and haematological cancers were screened for sensitivity to HDACi-induced apoptosis, and response correlated with IE gene induction. HDACi treatment robustly induced IE gene mRNA and protein expression in multiple tumour lines. IE gene induction was sustained over 24 hours and dependent on the Sp1/Sp3 transcription factors and was also observed in vivo in CTCL patients treated with the HDACi panobinostat. The magnitude of induction of FOS, JUN and ATF3 expression correlated significantly with HDACi-induced apoptosis. The induction of ATF3 was critical for HDACi induced apoptosis as ATF3 downregulation markedly attenuated HDACi-induced apoptosis in multiple tumour lines, and ATF3 knockout MEFs were refractory to HDACi-induced apoptosis. To identify downstream targets of ATF3, the magnitude of ATF3 induction following HDACi treatment was correlated with altered expression of pro and anti-apoptotic genes involved in the intrinsic apoptotic pathway. The magnitude of ATF3 induction correlated inversely with repression of the anti-apoptotic gene Bcl-XL, and ATF3 knockdown attenuated HDACi-mediated Bcl-XL repression. Notably, combinatorial treatment of refractory cell lines with an HDACi and a Bcl-XL inhibitor significantly enhanced HDACi-induced apoptosis. This study demonstrates that IE gene induction is a universal feature of HDACi-induced apoptosis, and that ATF3 as a key driver of HDACi-induced apoptosis through repression of Bcl-XL. These findings establish a method for rapid assessment of HDACi response, and identify a combination strategy for enhancing the activity of these compounds. Citation Format: Anderly C. Chueh, Janson Tse, Paul Ioannidis, Lars Tögel, Bee S. Tan, Mercedes Davlos-Salas, Rebecca Nightingale, Matthew R. Thompson, Bryan Williams, Michael Dickinson, Amardeep S. Dhillon, John M. Mariadason. Histone deacetylase inhibitors induce apoptosis in multiple tumor types through induction of ATF3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4728.

Genetics of Cutaneous T Cell Lymphoma: From Bench to Bedside.

Cutaneous T cell lymphomas (CTCLs) are non-Hodgkin lymphomas of skin homing T cells. Although early-stage disease may be limited to the skin, tumor cells in later stage disease can populate the blood, the lymph nodes, and the visceral organs. Unfortunately, there are few molecular biomarkers to guide diagnosis, staging, or treatment of CTCL. Diagnosis of CTCL can be challenging and requires the synthesis of clinical findings, histopathology, and T cell clonality studies; however, none of these tests are entirely sensitive or specific for CTCL. Treatment of CTCL is often empiric and is not typically based on specific molecular alterations, as is common in other cancers. In part, limitations in diagnosis and treatment selection reflect the limited insight into the genetic basis of CTCL. Recent next-generation sequencing has revolutionized our understanding of the mutational landscape in this disease. These analyses have uncovered ultraviolet radiation and recombination activating gene (RAG) endonucleases as important mutagens. Furthermore, these studies have revealed potentially targetable oncogenic mutations in the T cell receptor complex, NF-κB, and JAK-STAT signaling pathways. Collectively, these somatic mutations drive lymphomagenesis via cancer-promoting changes in proliferation, apoptosis, and T cell effector function. We expect that these genetic findings will launch a new era of precision medicine in CTCL.

Durable Responses With Maintenance Dose-Sparing Regimens of Romidepsin in Cutaneous T-Cell Lymphoma.

Romidepsin is a histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma (CTCL). Durable responses have been published without establishing a standard recommendation about duration of treatment. To review the long-term use of romidepsin in responders who received a dose-sparing regimen. Retrospective review of medical records of patients with a diagnosis of CTCL, including mycosis fungoides (MF), Sézary syndrome (SS), or CTCL not otherwise specified seen at a multidisciplinary clinic at Northwestern University from 2009 until December 2014. Doses administered and different regimens of romidepsin were reviewed. Duration of treatment, participants receiving dose-sparing regimen. Of 47 patients identified, 23 had MF, 15 had SS, and 9 had other types of CTCL. None of these 9 (mostly cytotoxic lymphomas) achieved a durable response. Of the remaining 38 patients, 17 were considered long-term responders (>6 months of treatment). Nine of these patients received a dose-sparing regimen. The median (range) duration of treatment was 15 (7-34) months; the frequency of patients with SS (10 of 15) in the long-term group was significantly higher than that of patients with MF (7 of 23; P = .046). Adverse events were reported in 29 (69%) of 42 patients for whom data were available. There was no significant difference in the incidence of AEs between the short-term and long-term groups (12 of 21 vs 12 of 17; P = .50). Decreasing the frequency of infusions in patients with MF or SS who achieve a response with romidepsin therapy may provide a practical strategy to prolong response.

Polish Lymphoma Research Group Experience With Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma.

Bexarotene, a synthetic retinoid licensed for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been used clinically in Poland since 2007 in 21 patients. The objective of our retrospective, multicenter study was to evaluate our experience with bexarotene therapy, including efficacy, safety, and survival outcomes. We retrospectively identified 21 adult patients who were treated with bexarotene between the years 2007 and 2012. Starting dose of bexarotene was 300 mg/m per day. The analysis included 3 patients with early-stage mycosis fungoides (MF), 16 patients with advanced-stage MF, and 2 patients with Sézary syndrome (SS). The mean duration of therapy with bexarotene was 14.5 months. Use of bexarotene resulted in an overall response rate of 81.0%, although the overall mortality rate was 52.8%. In our study, early-stage CTCL responded better than advanced-stage CTCL (100.0% vs. 77.8%, respectively). The mean time to observable response was 1.8 months, and the mean duration of the response was 16.4 months. Most significant side effects were hyperlipidemia, hypothyroidism, and a bleeding gastric ulcer. Based on the results of our analysis, bexarotene is a valuable tool in the treatment of refractory early-stage CTCL. Although a majority of patients initially responded to therapy, the high mortality rate in the advanced-stage group suggests that bexarotene does not completely resolve the therapeutic problems in all stages of CTCL. Patient stratification for bexarotene treatment may need a thorough reassessment, in that bexarotene may not be an effective drug in the very advanced stages of CTCL.

415. The Potency of a Histone Deacetylase Inhibitor and Reolysin in Head and Neck Squamous Cell Carcinoma

Introduction: There is a clear and pressing need for novel therapies with activity against locally advanced head and neck cancers which still carry a dismal prognosis. Oncolytic viruses are powerful, targeted anti-cancer agents. Reovirus is a naturally occurring non-pathogenic virus that was isolated from the human respiratory and gastrointestinal tracts. Moreover, Reovirus type 3 Dearing (Reolysin; Oncolytics Biotech Inc., Calgary, AB, Canada) is currently being tested in phase I-III clinical trials in a variety of tumor types. Histone deacetylase inhibitors (HDACi) comprise a structurally diverse class of compounds that are targeted anticancer agents. The first FDA approved HDACi, vorinostat (suberoylanilide hydroxamic acid-SAHA), is highly effective in the treatment of cutaneous Tcell lymphoma. SAHA is currently being testing in head and neck cancer clinical trials. We previously found a synergistic combination of SAHA and Reolysin in a nude mouse model. Preclinical models of oncolytics are often in immunocompromised mice, negating the significant impact of the immune system. Mounting evidence demonstrates that the immune system is critically important in oncolytic viral response. In this study, we sought to investigate the impact of this combination in an immunocompetent model. Methods: Cell survival experiments were performed with reovirus and SAHA in shPTP-BL-Ras SCC cells. IC50 values were interpolated from a sigmoidal dose-response curve fit of the log-transformed survival data. JAM-1 surface levels were assessed via flow cytometric analysis. Cells were collected after 48 hours and cell death was assessed via Annexin V and PI staining. JAM-1 levels were assessed using anti-JAM-1-PE staining as compared to a control isotype-PE antibody. Whole splenocytes were isolated at the time of death for C57BL/6 mice bearing MTE tumors treated in 4 groups (control, SAHA, reovirus, and combination). Three independent mice were stained per group for the following: B cells (CD19+), NK cells (CD49b+), activated NK cells (CD49b+NKp46+), dendritic cells (CD11c+) and activated DCs (CD11c+MHCII+ or CD11c+CD86+), CD4 T helper (CD3+CD4+), and CD8 cytotoxic cells (CD3+CD8+). Results: Experiments demonstrated significant efficacy of SAHA and Reolysin treatment in vitro and in the immunocompetent mouse model. Combination therapy exhibited a synergistic anti-tumor effect with a significant increased survival of mice compared to any of the agents alone. The Jam1 receptor was upregulated on tumor cells allowing enhanced reovirus uptake. There was marked and significant reduction in circulating B cells in combination treated mice versus all other groups. Activated NK cells were decreased in the combination group. T cells and dendritic cells (CD11c+MHCII+) were reduced in the SAHA groups. SAHA model withdrawal experiments show a significant synergistic response and immune system rebound after SAHA cessation. Conclusion: This data demonstrates that combination of reovirus plus SAHA therapy has significant activity in the treatment of SCCHN, even in an immunocompetent model. Immune inhibition due to SAHA as well as increased Jam1 receptor expression on tumor cells results in a synergistic effect of the combination therapy. Immune system rebound likely plays a significant role in the long-term anti-tumor response. This strong preclinical evidence supports the translation of this combination to phase-I clinical trials.

The Effects of Arsenic Trioxide in Combination with Retinoic Acids on Cutaneous T-Cell Lymphoma Cell Lines

Cutaneous T-cell lymphomas (CTCL) are characterized by an infiltration of the skin with malignant T cells. Curative treatments for aggressive entities such as Sézary syndrome have not been identified yet. Arsenic trioxide (AsO₃) is used for the treatment of acute promyelocytic leukemia in combination with retinoids. As the latter are established treatment options in CTCL, we sought to evaluate the efficacy of AsO₃ for mono- and combination therapy in vitro. Analyses for apoptosis, cell cycle inhibition, cytotoxicity and cell viability were made after incubation of CTCL cells with AsO₃ alone or in combination with the retinoids all-trans-retinoic acid or bexarotene. While AsO₃ induced apoptosis, retinoids did not at the time point of analysis. However, retinoids strongly reduced cell viability. Due to the efficient apoptosis induction, AsO₃ might be a potentially suitable agent for CTCL treatment, although this effect was not increased by retinoids.

Mogamulizumab for the treatment of cutaneous T-cell lymphoma: recent advances and clinical potential.

Mogamulizumab (KW-0761) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets CC chemokine receptor 4 (CCR4). It has shown promising therapeutic potential in phase I and II clinical trials and is currently being investigated for efficacy in treating cutaneous T-cell lymphoma (CTCL). We review the mechanism of action of mogamulizumab and its role in treating CTCL. We also discuss the results of major clinical trials.

Cutaneous T-Cell Lymphoma: A Review with a Focus on Targeted Agents.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of extranodal lymphomas involving the skin. Diagnosis of the two main subtypes of CTCL-mycosis fungoides (MF) and Sézary syndrome (SS)-is based on the International Society for Cutaneous Lymphomas/European Organization for Research and Treatment of Cancer (ISCL/EORTC) classification system, which utilizes clinical, histopathological, molecular biologic, and immunopathologic features. Risk stratification, based on TNMB (tumor, node, metastasis, and blood) staging, provides prognostic information, with limited-stage disease conferring the longest median overall survival. Skin-directed therapies are preferred in the management of limited-stage disease, whereas advanced-stage disease requires systemic therapies. As the mechanisms of CTCL pathogenesis are increasingly understood, new monoclonal antibodies, checkpoint inhibitors, immunomodulatory agents, and small molecules are under investigation and may provide additional therapeutic options for those with advanced CTCL. This review examines the current landscape of targeted therapies in the treatment of CTCLs.

Epigenetics in cutaneous T-cell lymphoma

Epigenetics means heritable changes in gene expressions without alterations in DNA sequence, and mainly involves DNA methylation, histone modification and non-coding RNA regulation. Cutaneous T-cell lymphoma is a class of malignant T-cell lymphoproliferative diseases originated from the skin. Mycosis fungoides and Sezary syndrome are the most common cutaneous T-cell lymphoma. Recent studies have shown that epigenetics not only plays an important role in the occurrence and development of cutaneous T-cell lymphoma, but also provides insights into the treatment of cutaneous T-cell lymphoma. Key words: Lymphoma, T-cell, cutaneous; Epigenesis, genetic; Mycosis fungoides; Sezary syndrome; DNA methylation

The Therapeutic Potential of AN-7, a Novel Histone Deacetylase Inhibitor, for Treatment of Mycosis Fungoides/Sezary Syndrome Alone or with Doxorubicin.

The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H3, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS.