scholarly journals GSK458 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in T Cell Lymphomas As a Single Agent and in Combination Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5378-5378 ◽  
Author(s):  
Juan Gu ◽  
Lianjuan Yang ◽  
Dennis C Gaughan ◽  
Ling He ◽  
Weina Shen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
T Cell Lymphoma ◽  
Synergistic Activity ◽  
T Cell Lymphomas

Abstract Introduction: T-cell lymphoma (TCL) accounts approximately 15% of all Non-Hodgkin's lymphoma cases. TCL are often divided into either systemic or cutaneous TCL (CTCL). The management of TCL systemic or cutaneous is challenging because the emergence of chemotherapy resistance that lead to early death (systemic T-cell lymphomas) or chronic debilitating clinical course (CTCL). To improve the clinical outcomes and reduce treatment-related toxicity, research need to be done focusing on understanding and targeting the molecular mechanism driving TCL subtypes. Recently, studies showed that the PI3K AKT/mTOR pathway was activated in TCL. GSK458 is a potent oral dual inhibitor of pan PI3K (α, β, γ and δ) and mTOR (mTOR1 and mTOR2). Preclinical studies in B-cell lymphomas showed GSK458 had broad antitumor activity in vitro and in vivo. In 2016, Phase I clinical trial of GSK458 was competed at the maximal dosage of 2.5mg twice daily. However, the effects of GSK458 on T-cell malignancies remain utterly unknown. Here, we evaluated the activity of GSK458 in preclinical T cell lymphoma models. Methods: We used a panel of T-cell lymphoma cell lines representing PTCL (J45), T-cell lymphoblastic lymphoma (SupT-1), and Mycosis Fungoides (MF)(MJ, HH and H9). TCL cell lines were exposed to escalating doses of GSK458 (1nM-100µM) without or with chemotherapeutic agents (doxorubicin, cisplatin, carboplatin, and dexamethasone); Bcl-2 inhibitor (Venetoclax); proteasome inhibitors ( bortezomib, carfilzomib, Ixazomib); or HDAC inhibitors (SAHA) for 48 and 72 hrs. Differences in cell viability, ATP levels, low mitochondria potential, glucose update, apoptosis and cell cycle distribution were evaluated utilizing PrestoBlue, Cell-Titer Glo assays, DiOC6, 2-NDG, Annexin V and propidium iodide staining followed by flow cytometric analysis, respectively. IC50 was calculated by GraphPad. PI3K and mTOR downstream pathway phosphorylation status, such as p-AKT Ser473, p-AKT Thr308, p-mTOR and p-GSK3β were detected by internally staining of FITC conjugated-antibodies followed by flow cytometry. Apoptosis proteins (MCL-1, PARP, p53, XIAP etc.) were detected by western blot. The additive/synergistic activity of GSK458 was detected by presto blue assay and Coefficient of synergy was calculated using CalcuSyn. Results:In vitro exposure of TCL cell lines to GSK458 demonstrated a dose- and time-dependent cell death. The IC50 of the cells were ranged from 3nM to 1.05uM at 72 hours. At 72h, GSK458 10nM lowered cellular mitochondrial potential, ATP levels and glucose uptake. GSK458 induced apoptosis and arrested the cell cycle at G1. At molecular level, GSK458 reduced phosphorylation status of AKT ser473 and Thr308, mTOR and GSK3β. Interestingly, GSK458 inhibited Mcl-1 expression level. GSK458 exhibited synergistic activity when combined with doxorubicin and dexamethasone. To a lesser degree, GSK458 enhanced the anti-tumor activity of Venetoclax, proteasome and HDAc inhibitors. Conclusion: GSK458 is active as a single agent or in combination with chemotherapy agents or small molecule inhibitors in a variety of T-cell pre-clinical models representing forms of systemic or cutaneous T-cell lymphoma. GSK458 was able to inhibit phosphorylation of AKT, mTOR and GSK3β, which may be the mechanism to reduce ATP production and glucose uptake in the cancer cells. Moreover, GSK458 arrested cell cycle at G1 arrest. Our data supports the clinical evaluation of GSK458 in relapsed/refractory T-cell lymphoma patients. (Supported by Roswell Park Cancer Institute Alliance Foundation Grant) Disclosures No relevant conflicts of interest to declare.

Combination of Epigenetic Agents Synergistically Reverse the Malignant Phenotype in Models of T-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2727-2727 ◽  
Author(s):  
Enrica Marchi ◽  
Matko Kalac ◽  
Danielle C Bongero ◽  
Christine M McIntosh ◽  
Laura K Fogli ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Molecular Level ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Combination Group ◽  
T Cell Lymphomas

Abstract Abstract 2727 CHOP and CHOP-like chemotherapy remain the most commonly used regimens for the treatment of peripheral T-cell lymphomas (PTCLs) despite sub-optimal results. Histone deacetylase inhibitors (HDACIs) are presently approved for the treatment of relapsed or refractory cutaneous T- cell lymphomas (CTCL) and peripheral T-cell lymphomas (PTCL) given their marked single agent activity in these diseases. The interaction between the HDACIs (depsipeptide (R) and belinostat (B)) and a DNMT inhibitor (decitabine (D)) was investigated in vitro, in vivo and at the molecular level in different T-cell lymphoma and leukemia cell lines including CTCL (H9, HH), and T- acute lymphoblastic leukemia (T-ALL) lines resistant to gamma-secretase inhibitors (P12, PF-382). For all cytotoxicity assays, a luminescence based cell viability assay was used (CellTiter-Glo™) followed by acquisition on a Biotek Synergy HT. Drug: drug interactions were analyzed using the calculation of the relative risk ratios (RRR<1 are defining synergism). Apoptosis was assessed by staining with Yo-Pro-1 and propidium iodine followed by FACSCalibur acquisition and analyzed using FlowJo. The IC50s for B, R, vorinostat (V), panobinostat (P), D and 5-Azacytidine alone were assessed at 24, 48 and 72 hours in all the cell lines. For the combination experiment we selected the most active DNMTI, decitabine. In the cytotoxicity assays, the combination of D plus B, R, V or P at 72 hours showed synergism in all the cell lines studied. The RRRs for all the combinations were between 0.0007 and 0.9. When H9, HH, P12 and PF382 cell lines were treated with D and B or R for 72 hours, all the combination groups showed significantly more apoptosis than the single drug exposures and controls. Table 1 displays the range of apoptosis induction for B, R ± D and the RRR value for the most significant data.Table 1:BDB + DRRR(% Apoptotic + Dead Cells)H9100 nM (22.9%)500 nM (17.9%)51.5%0.7HH100 nM (42.9%)1 uM (46.9%)61.3%0.8P 12150 nM (16%)1 uM (42.7%)80.1%0.4PF 382100 nM (8.3%)1 uM (27.9%)40.1%0.8RDR + DH92 nM (22.2%)500 nM (17.9%)63.6%0.5HH2 nM (80%)1 uM (46.9%)89.7%0.6P 122 nM (9.9%)10 uM (58.7%)98%0.03PF 3822 nM (54.5%)500 nM (17.9%)88.7%0.2 An in vivo xenograft study in 6–8 weeks old female SCID beige mice injected subcutaneously with 2 × 107 HH cells was performed. Mice were separated into different cohorts and treated i.p. for 3 cycles with D or B or their combination according to the following schedules: D at 1.5 mg/kg on days 1, 3, 5; B at 40 mg/kg/day for 10 days (I cycle); D at 1.5mg/kg on days 15,17,19,21; B at 65 mg/kg/day for 10 days (II cycle); D at 1.5 mg/kg on days 29,31,33,35,37,39,41,43; B at 100mg/kg for 19 days (III cycle). Statistically significantly tumor growth inhibition was observed in the combination cohort compared to all the other cohorts (analysis on day 42, 45). We analyzed the molecular basis for this synergistic effect by evaluating gene expression patterns using the Illumina Human HT-12 v4 Expression BeadChip microarrays. These analyses revealed differentially expressed genes and modulated pathways for each of the single treatment conditions and the combination. As shown in Figure 1, a set of genes (A) is down-regulated by both drugs. Other genes (B) are up-regulated by D and the effect is maintained in the combination. Other genes (C+E) are slightly up-regulated by R, though not significantly modified by D, and more strongly up-regulated in the combination group. Similarly, genes to some extent up-regulated by D but not by R (D+F) appeared to be more significantly affected by the combination. As shown in Figure 2, the effects of the two drugs are largely different (only 39 genes modified in common by all the treatment groups). Most of the effects induced by the single agent treatment are maintained in the combination group (174 genes out of 191 for romidepsin and 211 genes out of 221 for decitabine). Interestingly, an additional 944 genes appeared to be modulated uniquely by the combination treatment strongly supporting the hypothesis of synergism also at the molecular level. Collectively, the data suggest that the combination of a DNMTI and HDACIs is synergistic in in vitro and in vivo model of T-cell lymphoma and is able to synergistically reverse the malignant signature at the molecular level. These data may constitute the basis for future phase I-II clinical trials. Disclosures: O'Connor: celgene: Consultancy, Research Funding; merck: Research Funding; Novartis: Research Funding; spectrum: Research Funding.

scholarly journals MK2a Substrate-Selective p38 Inhibitor CMPD1 Selectively Synergizes with HDAC Inhibitors in CD34+ Cells from Myeloid Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2239-2239
Author(s):  
James M Bogenberger ◽  
Nanna Hansen ◽  
Devora Delman ◽  
Ruben A. Mesa ◽  
Raoul Tibes
Keyword(s):  
T Cell ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
T Cell Lymphoma ◽  
Myeloid Malignancies ◽  
P38 Inhibitor

Abstract Background: Histone deacetylase (HDAC) inhibitors (HDIs) vorinostat (SAHA) and romidepsin are approved for the treatment of cutaneous T-cell lymphoma, while belinostat has recently been approved for the treatment of peripheral T-cell lymphoma. SAHA exhibits clinical activity in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), although insufficient to justify single-agent therapy for these indications. The precise clinical mechanism of SAHA and other HDIs remains incompletely characterized, impeding the design and implementation of rational HDI-based therapeutic combinations for myeloid malignancies. To circumvent this lack of mechanistic understanding, we conducted RNA-interference (RNAi) modifier screens of the kinome and phosphatome to identify signaling pathways that modulate SAHA (HDI) anti-leukemic activity in AML cell lines TF-1, HEL and THP-1 for rapid translation of findings from ex vivo validation to clinical application. Results: Multiple screen hits (both kinases and phosphatases) converge on distinct points of the p38-SAPK/JNK signaling pathways, suggesting involvement of these stress-activated pathways in SAHA anti-leukemic activity. However, the most well characterized p38α/β inhibitors SB202190 and LY2228820 do not augment SAHA anti-leukemic activity at any dose across the broad dose ranges tested. Similarly, the JNK inhibitor SP600125 does not modulate SAHA activity at doses that inhibit JNK. However, the putative MK2a substrate-selective p38 inhibitor CMPD1 (Boehringer-Ingelheim; Davidson, W., et. al., Biochemistry 2004 Sep 21;43(37):11658-71) selectively potentiates the activity of SAHA in all AML cell lines tested (N=8), as well as in ex vivo cultures of primary myeloid malignancies (N=14), including polycythemia vera, chronic myelomonocytic leukemia, MDS/myeloproliferative neoplasm overlap syndrome, MDS transformed to AML, and de novo AML. The observed dose-dependent synergy occurs at nanomolar doses consistent with the reported apparent inhibitory constant for CMPD1 inhibition of p38-dependent phosphorylation of MK2a. Further, SAHA + CMPD1 synergy is significantly greater in CD34+-selected as compared to CD34+-depleted cell populations ex vivo. Furthermore, CMPD1 is similarly synergistic with the HDI panobinostat in vitro, but interacts antagonistically with cytarabine and additively with 5-azacitidine. This suggests that CMPD1 interacts specifically with SAHA and panobinostat in AML. The synergistic interaction between CMPD1 and SAHA is independent of ROS induction, as pretreatment with N-acetylcysteine does not abrogate synergy, despite reducing single-agent SAHA activity. While CMPD1 is reported to be an MK2a substrate-selective p38 inhibitor, CMPD1 does not affect the regulation of several canonical MK2 targets at doses that are potently synergistic in AML cell lines, including the phosphorylation of HSP27 or AATF. To begin to probe the mechanism of CMPD1 and SAHA synergy more extensively, mRNA expression was measured by next-generation sequencing after SAHA and CMPD1 treatment alone and in combination in the AML cell line TF-1. Sequencing data is currently being analyzed and findings will be presented. Conclusion: RNAi knockdown of several p38-SAPK/JNK pathway components modulates SAHA activity in malignant myeloid cells; however, common pharmacological sensitizing targets remain elusive. We hypothesize that MK2 and/or a yet unrecognized pathway modulated by CMPD1 can be targeted for HDI combination therapy in malignant myeloid cells. Current and ongoing results from this study will provide validated targets for rational HDI combination in myeloid malignancies. Disclosures Off Label Use: LDE225/Sonidegib as investigational agent. Mesa:Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding.

Results From a Prospective, Open-Label, Phase II Trial of Bendamustine in Refractory or Relapsed T-Cell Lymphomas: The BENTLY Trial

2013 ◽  
Vol 31 (1) ◽  
pp. 104-110 ◽  
Author(s):  
Gandhi Damaj ◽  
Rémy Gressin ◽  
Krimo Bouabdallah ◽  
Guillaume Cartron ◽  
Bachra Choufi ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Open Label ◽  
Previous Response ◽  
Angioimmunoblastic Lymphadenopathy ◽  
Prior Chemotherapy ◽  
T Cell Lymphomas

Purpose To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas. Patients and Methods Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m2 per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%). Conclusion Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.

Effect of a combination of epigenetic agents on the malignant phenotype in models of T-cell lymphoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13569-e13569
Author(s):  
Enrica Marchi ◽  
Matko Kalac ◽  
Danielle Bongero ◽  
Christine McIntosh ◽  
Laura K Fogli ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lines ◽  
Molecular Level ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Cytotoxicity Assays

e13569 Background: CHOP and CHOP-like chemotherapy are the most used regimens for the treatment of peripheral T-cell lymphomas (PTCLs) despite sub-optimal results. Histone deacetylase inhibitors (HDACIs) have shown class activity in PTCLs. The interaction between the HDACIs (depsipeptide (R), belinostat (B), vorinostat (V) and panobinostat (P)) and a DNMT inhibitor (decitabine (D) was investigated in vitro, in vivo and at the molecular level in T-cell lymphoma and leukemia cell lines (H9, HH, P12, PF-382). Methods: For cytotoxicity assays, luminescence cell viability assay was used (CellTiter-Glo). Drug:drug interactions were analyzed with relative risk ratios (RRR) based on the GraphPad software (RRR<1 defining synergism). Apoptosis was assessed by Yo-Pro-1 and propidium iodine followed by FACSCalibur acquisition. Gene expression profiling was analyzed using Illumina Human HT-12 v4 Expression BeadChip microarrays and Gene Spring Software for the analysis. Results: The IC50s for B, R, V, P, D and 5-Azacytidine alone were assessed at 24, 48 and 72 hours. In cytotoxicity assays the combination of D plus B, R, V or P at 72 hours showed synergism in all the cell lines (RRRs 0.0007-0.9). All the cell lines were treated with D, B or R for 72 hours and all the combinations showed significantly more apoptosis than the single drug exposures and controls (RRR < 1). In vivo, HH SCID beige mice were treated i.p. for 3 cycles with the vehicle solution, D or B or their combination at increasing dose. The combination cohort showed statistically significant tumor growth inhibition compared to all the other cohorts. Gene expression analysis revealed differentially expressed genes and modulated pathways for each of the single agent treatment and the combination. The effects of the two drugs were largely different (only 39 genes modified in common). Most of the effects induced by the single agent were maintained in the combination group. Interestingly, 944 genes were modulated uniquely by the combination treatment. Conclusions: The combination of a DNMTI and HDACIs is strongly synergistic in vitro, in vivo and at the molecular level in model of T-cell lymphoma and these data will constitute the basis for a phase I-II clinical trials.

Multicenter, phase II study of bendamustine in refractory or relapsed T-cell lymphoma: The BENTLY trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8026-8026 ◽  
Author(s):  
Remy Gressin ◽  
Gandhi Laurent Damaj ◽  
Kamal Bouabdallah ◽  
Guillaume Cartron ◽  
B Choufi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Single Agent ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Previous Response ◽  
T Cell Lymphomas

8026 Background: T-cell lymphomas have a poor prognosis with few options of effective treatment. This study determined the efficacy and safety of bendamustine as a single agent in the treatment of refractory or relapsed T-cell lymphomas. Methods: Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL), who had previously received at least one line of chemotherapy were selected. Bendamustine was administered IV at the dosage of 120 mg/m2 on days 1 and 2 every 3 weeks, for 6 cycles. Treatment response was assessed using the IWC for non-Hodgkin's lymphoma. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DoR), progression-free survival (PFS), and overall survival (OS), NCT00959686. Results: Twenty two female and 38 male were included. The median age was 66 years with more 1/4 of them > 75. Histology was predominantly angio-immunoblastic lymphadenopathy (n=32) and PTCL-nos (n=23). The median previous line of chemotherapy was 1 (1-3). Nearly one half (45%) of the patients was refractory to the last previous chemotherapy and the median duration of the best previous response was 6.6 (1.5-67) months. The disease was disseminated in the majority of case (87%) and the international prognostic index (IPI) was high (3–5) in 68% of the patients. Twenty patients (33%) received less than 3 cycles of bendamustine. The major reason for early discontinuation was disease progression. In the Intent-To-Treat (ITT) population, the best ORR was 50%, including complete response (CR) in 28% and partial response (PR) in 22 %. Bendamustine showed a consistency in the efficacy as a function of major disease characteristics. The median values for DoR, PFS and OS were 3.5, 4 and 6 months respectively. The most frequent grade 3/4 AEs were neutropenia (30%), thrombocytopenia (24%) and infections (20%). Conclusions: Bendamustine is active in high risk refractory and relapsed T-cell lymphoma with manageable toxicity.

Epigenetic Modulation and Therapy of Lymphoid Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-30-SCI-30
Author(s):  
Susan E. Bates
Keyword(s):  
T Cell ◽  
Histone Acetylation ◽  
Gene Transcription ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
Dna Methyltransferases ◽  
T Cell Lymphoma ◽  
Clinical Samples ◽  
Clinical Activity ◽  
T Cell Lymphomas

Abstract Abstract SCI-30 The FDA has approved four epigenetic therapies for oncology: Vidaza™ (azacitidine, 2004), Dacogen® (decitabine, 5-aza-2′-deoxycytidine, 2006), Zolinza™ (vorinostat, 2006), and Istodax® (romidepsin, 2009); and many more are in clinical and preclinical development. While we know the enzymatic targets of these agents, we still do not fully understand the true mechanism of action of these agents. Ostensibly, both classes of agents work to inhibit enzymes that silence genes with tumor suppressor function: DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Reduction of hypermethylation has been documented following inhibition of DNMT by 5-aza-2-deoxycytidine and 5-azacytidine. Significant clinical activity including durable responses and improvement in survival initially led to approval of these agents in myelodysplastic syndrome (MDS). Although demethylation has been confirmed following treatment with these agents, particularly in the low dose, chronic schedule developed for MDS, the extent of demethylation does not correlate with response, suggesting other factors are important. The genes critical for response are still under study – several known to be hypermethylated in MDS have been intensively studied, including the p15INK4B and the fragile histidine triad (FHIT) genes. There are many parallels for the HDAC inhibitors, which also inhibit enzyme activity and promote gene transcription. FDA approvals for vorinostat and romidepsin are based on clinical activity in cutaneous T-cell lymphoma (CTCL) including durable and complete responses. Activity in peripheral T-cell lymphomas has also been observed in clinical trials with romidepsin and other HDAC inhibitors. Increased global histone acetylation has been noted in clinical samples; however, there is no correlation of this marker with response to vorinostat. Romidepsin, on the other hand, requires activation and our clinical data have suggested a correlation between persistent histone acetylation and clinical response. The gene alterations critical for clinical activity still require definition. Although HDAC inhibitors reliably induce the CDK inhibitor p21, overall about 5% of genes assayed are upregulated by HDAC inhibitors in array studies, and an equal number downregulated. Notably, multiple cellular proteins are also affected by acetylation; some of them potentially responsible for the activity of the HDAC inhibitors. This may depend upon cellular context but in some cell types is likely to be as important if not more important than their effects on gene transcription. T-cell lymphomas in more than one-third of patients show sensitivity to the HDAC inhibitors, and it is not known which of the myriad activities is critical for the activity in the T-cell lymphomas. What we do know is that in a subset of patients, responses can be very good, and of very long duration. Critical needs for epigenetic therapies include a more precise determination of mechanisms of action, so that we may identify the subsets of patients who will have disease response. We need to define mechanisms of resistance that emerge after treatment fails if we hope to prevent that outcome. We need effective combinations with epigenetic therapies to increase their activity in the diseases currently known to be susceptible, but also to extend their range of activity. Epigenetic therapies – originally identified as differentiating agents – are unique among anticancer therapies in having the potential to actually reset the oncogenic phenotype. A significant research effort is needed to harness this potential. Disclosures: Bates: Gloucester Pharmaceuticals: Research Funding. Off Label Use: romidepsin efficacy in peripheral T cell lymphoma is experimental but efficacy data are available.

scholarly journals 2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T- cell lymphoma

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 587-592 ◽  
Author(s):  
A Saven ◽  
CJ Carrera ◽  
DA Carson ◽  
E Beutler ◽  
LD Piro
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Active Agent ◽  
T Cell Lymphoma ◽  
Treatment Modalities ◽  
Cutaneous T Cell Lymphoma ◽  
T Cell Lymphomas ◽  
Duration Of Response ◽  
Combination Regimens

Abstract Cutaneous T-cell lymphomas are disfiguring malignant lymphoproliferative disorders for which standard therapy has been principally palliative. 2-Chlorodeoxyadenosine (2-CdA), a new purine analogue resistant to degradation by adenosine deaminase that has substantial activity against lymphoid neoplasms, was administered to 16 patients with cutaneous involvement by T-cell lymphoma. All patients had failed topical treatment modalities and/or systemic therapies. Fifteen patients were evaluable; one patient was not evaluable due to incomplete therapy and follow-up. The overall response rate was 47%. Three of 15 patients (20%) achieved complete responses and four of 15 patients (27%) achieved partial responses. The median duration of response was 5 months. One patient remains in unmaintained complete remission at 52+ months. Therapy was well tolerated. Myelosuppression was the principal toxicity encountered, occurring in 8 of 15 (53%) patients. 2-CdA is an effective new agent for the treatment of cutaneous T-cell lymphoma and warrants further study both as a single agent and in combination regimens.

scholarly journals Selective Inhibition of HDAC6 Decreases Viability of Cutaneous T-Cell Lymphoma and Improves Immune Recognition

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5423-5423
Author(s):  
Tessa Knox ◽  
Maritza Lienlaf ◽  
Patricio Perez-Villarroel ◽  
Calvin Lee ◽  
Eva Sahakian ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Cell Biology ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
T Cell Lymphoma ◽  
Immune Recognition ◽  
Cutaneous T Cell Lymphoma ◽  
Inhibition Of Proliferation

Abstract Cutaneous T-cell lymphoma (CTCL) includes a spectrum of non-Hodgkin’s T-cell lymphomas. While most patients with CTCL experience non-life threatening skin symptoms, those who do progress to later stages of the disease may develop serious complications. For patients with tumor stage or lymph node involvement there is a significant decline in treatment response & few treatment options are available. Current available therapeutic options include the use of histone deacetylase (HDAC) inhibitors as Romidepsin, Panobinostat and Vorinostat. However, their mechanism of action is still unknown. The role of histone deacetylases (HDACs) in cell biology, initially limited to their effects upon histones, now encompasses more complex regulatory functions that are dependent on their tissue expression, cellular compartment distribution, pathophysiological conditions and stage of cellular differentiation. Although major advances have been made in understanding the role of specific HDACs in cell proliferation and the survival of cancer cells, their individual participation in specific intracellular pathways is not completely understood. Here we present data demonstrating the changes in several immune-related pathways in two CTCL cell lines after exposure to both pan-HDAC inhibitors and selective HDAC6 inhibitors. We compared the pharmacological effects of the pan-HDAC inhibitor LBH589 (Panbinostat), the class I selective Romidepsin, and the selective HDAC6 inhibitors such as TubastatinA and NexturstatB, on two CTCL cell lines (HuT78, HuT102). Our findings thus far demonstrate the following: First, we observed a marked inhibition of proliferation capacity of both cell lines when treated with either pan-HDACi or the more selective HDAC6 inhibitors. However, the selective HDAC6 inhibitors showed less cytotoxicity. Second, we observed important changes in the expression of the co-inhibitory molecules, such as PD-L1. Given our results, we conclude that the selective targeting of HDAC6 could recapitulate the anti-tumor effects of pan-HDAC inhibitors without having the non-target cytotoxic effects often encountered when using pan-HDAC inhibitors. Disclosures No relevant conflicts of interest to declare.

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