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Current Oncology Reports Mar 2018Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Globally, the most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCL can... (Review)
Review
PURPOSE OF REVIEW
Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Globally, the most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. CTCL can confer significant morbidity and even mortality in advanced disease. Here we review the current and potential future treatments for advanced-stage CTCL.
RECENT FINDINGS
Heterogeneity of treatment choice has been demonstrated both in US and non-US centers. Systemic treatment choice is currently guided by prognostic features, incorporating stage, immunophenotypic and molecular findings, and patient-specific factors such as age and comorbidities. Randomized controlled studies are uncommon, and the literature is composed predominantly of retrospective, cohort, and early-phase studies. International consensus guidelines are available; however, the lack of comparative trials means that there is no clear algorithmic approach to treatment. This review article reports on the systemic treatment options in current use for advanced CTCL, and on the possible future therapies, acknowledging that an algorithmic approach is not yet forthcoming to guide treatment prioritization.
Topics: Combined Modality Therapy; Humans; Mycosis Fungoides; Prognosis; Sezary Syndrome; Skin Neoplasms
PubMed: 29572582
DOI: 10.1007/s11912-018-0678-x -
Current Hematologic Malignancy Reports Feb 2018Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past... (Review)
Review
PURPOSE OF REVIEW
Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity. Herein we will review some of the latest developments.
RECENT FINDINGS
With the new WHO classification, discrete entities of PTCL are now being identified by molecular and phenotypic markers. This new classification is critical to our ability to define disease entities which may respond to certain classes of targeted therapy. Some such mutations include genes controlling epigenetics (TET2, IDH2, DNMT3A, RHOA, CD28). As such, epigenetic therapies such as histone deacetylase (HDAC) inhibitors have become the platform to which other novel therapies or chemotherapy has been added. Early phase clinical studies have demonstrated that combination therapy with romidepsin plus other agents known to have activity in T cell lymphoma have enhanced clinical benefit for this group of diseases. In addition, the antibody drug conjugate, brentuximab vedotin has been shown to have potent activity in T cell lymphomas expressing CD30. This drug is being studied as well with other targeted therapies and chemotherapy in an effort to improve response rates and progression-free survival. Although T cell lymphomas remain a highly challenging group of diseases to treat, new efforts to leverage drugs that discretely target the biology that drives T cell lymphomagenesis in combination provide hope that improved outcomes may be realized in the near future.
Topics: Combined Modality Therapy; Disease-Free Survival; Humans; Lymphoma, T-Cell, Peripheral; Mutation; Neoplasm Proteins; Survival Rate
PubMed: 29397528
DOI: 10.1007/s11899-018-0432-3 -
Current Opinion in Oncology Sep 2018Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell and natural killer (NK)-cell neoplasms in the WHO 2016 classification. Patient prognosis is... (Review)
Review
PURPOSE OF REVIEW
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell and natural killer (NK)-cell neoplasms in the WHO 2016 classification. Patient prognosis is poor when treated with CHOP, and there is an unmet need for new drugs. Several agents have been developed for PTCL, and their use is the subject of this review.
RECENT FINDINGS
Phase 2 studies demonstrated the activity of new drugs in Relapsed/refractory PTCL. Only four compounds were approved by the food and drug administration: romidepsin and belinostat, which are epigenetic modifiers, the antifolate agent pralatrexate, the immuno-conjugate brentuximab vedotin. New combinations have been tested, but the results were disappointing. Given the latest progress in biology, targeted agents are evaluated in different subtypes of PTCL. Relapsed anaplastic large-cell lymphoma exhibits improved prognosis with the approved anti-CD30 drug conjugate brentuximab vedotin. Localized nasal NK/T is treated with radiotherapy and nonanthracycline chemotherapy with L-asparaginase. Recently, immune checkpoint inhibitors demonstrated activity in NK/T lymphoma and can be used in elderly patients.
SUMMARY
Treatment remains a challenge for PTCL, and several targeted drugs provide new approaches. Progress will be made incrementally in the different subtypes. One of the critical situations facing new drugs is the ability to run robust clinical trials in rare diseases.
Topics: Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Clinical Trials, Phase II as Topic; Depsipeptides; Humans; Hydroxamic Acids; Immunoconjugates; Lymphoma, T-Cell, Peripheral; Randomized Controlled Trials as Topic; Sulfonamides
PubMed: 30096094
DOI: 10.1097/CCO.0000000000000469 -
Critical Reviews in Oncology/hematology Mar 2016Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of patients developing relapsed/refractory disease. Prior to 2009,... (Review)
Review
Peripheral T-cell lymphomas (PTCLs) tend to be aggressive and chemorefractory, with about 70% of patients developing relapsed/refractory disease. Prior to 2009, chemotherapies were the only options for relapsed/refractory PTCL, other than hematopoietic transplants. However, chemotherapy only improves survival by about 1 month compared with palliation. Four drugs are now approved in the US to treat relapsed/refractory PTCL: pralatrexate, romidepsin, belinostat, and brentuximab vedotin (for systemic anaplastic large cell lymphoma [sALCL]). Response rates with pralatrexate, romidepsin, and belinostat range from 25 to 54% in mixed relapsed/refractory PTCL populations, while 86% of sALCL patients respond to brentuximab vedotin. Here, we critically evaluate the evidence supporting the current drug treatment of relapsed/refractory PTCL, and look to the future to see how the treatment panorama may change with the advent of new targeted therapies, some of which (e.g., alisertib in PTCL and mogamulizumab in CCR4-positive adult T-cell leukemia/lymphoma) are already in phase 3 trials.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Salvage Therapy
PubMed: 26811013
DOI: 10.1016/j.critrevonc.2015.12.016 -
Hepatology Communications Jun 2022During the pandemic, dexamethasone (DEX), remdesivir (RDV), hydroxychloroquine (HCQ), thapsigargin (TG), camostat mesylate (CaM), and pralatrexate were repurposed drugs...
During the pandemic, dexamethasone (DEX), remdesivir (RDV), hydroxychloroquine (HCQ), thapsigargin (TG), camostat mesylate (CaM), and pralatrexate were repurposed drugs for coronavirus disease 2019 (COVID-19). However, the side effects on the liver associated with the anti-COVID therapies are unknown. Cellular stresses by these drugs at 0-30 μM were studied using HepG2, Huh7, and/or primary human hepatocytes. DEX or RDV induced endoplasmic reticulum stress with increased X-box binding protein 1 and autophagic response with increased accumulation of microtubule-associated protein 1A/1B-light chain 3 (LC3-II). DEX and RDV had additive effects on the stress responses in the liver cells, which further increased expression of activating transcription factor 4 and C/EBP homology protein 1 (CHOP), and cell death. Alcohol pretreatment (50 mM) and DEX induced greater cellular stress responses than DEX and RDV. Pralatrexate induced Golgi fragmentation, cell cycle arrest at G0/G1 phase, activations of poly (ADP-ribose) polymerase-1 (PARP) and caspases, and cell death. Pralatrexate and alcohol had synergistic effects on the cell death mediators of Bim, caspase3, and PARP. The protease inhibitor CaM and TG induced autophagic response and mitochondrial stress with altered mitochondrial membrane potential, B-cell lymphoma 2, and cytochrome C. TG and HCQ induced autophagic response markers of Unc-51 like autophagy activating kinase, LC3-II, Beclin1, and Atg5, and severe ER stress marker CHOP. Conclusion: These results suggest that the anti-COVID-19 drugs, especially with drug-drug or alcohol-drug combinations, cause cellular stress responses and injuries in the liver cells.
Topics: Endoplasmic Reticulum Stress; Ethanol; Hepatocytes; Humans; Microtubule-Associated Proteins; Poly(ADP-ribose) Polymerase Inhibitors; Thapsigargin; Transcription Factor CHOP; COVID-19 Drug Treatment
PubMed: 34910385
DOI: 10.1002/hep4.1887 -
Current Hematologic Malignancy Reports Dec 2015Mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), are malignancies of skin-homing T cells that comprise the majority of cutaneous T cell lymphomas... (Review)
Review
Mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), are malignancies of skin-homing T cells that comprise the majority of cutaneous T cell lymphomas (CTCL). Treatment of CTCL is limited and can be approached by skin-directed therapy or systemic therapy. Recent investigations into the pathogenesis of MF and SS have broadened the therapeutic targets; here, we review emerging concepts in the pathogenesis of MF and SS as well as novel and traditional systemic therapies for MF and SS. These include histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, and belinostat), monoclonal antibodies (alemtuzumab, brentuximab vedotin, and mogamulizumab) and single-agent cytotoxic chemotherapeutic agents (e.g., pralatrexate, doxorubicin, bendamustine, and forodesine), as well as multi-agent chemotherapy regimens.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides
PubMed: 26626770
DOI: 10.1007/s11899-015-0293-y -
Frontiers in Microbiology 2021Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the... (Review)
Review
Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the efficiency of screening of antimicrobial compounds against a broad spectrum of pathogens, deep learning has also the potential to efficiently and reliably identify drug candidates against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Consequently, deep learning has been successfully used for the identification of a number of potential drugs against SARS-CoV-2, including Atazanavir, Remdesivir, Kaletra, Enalaprilat, Venetoclax, Posaconazole, Daclatasvir, Ombitasvir, Toremifene, Niclosamide, Dexamethasone, Indomethacin, Pralatrexate, Azithromycin, Palmatine, and Sauchinone. This mini-review discusses recent advances and future perspectives of deep learning-based SARS-CoV-2 drug discovery.
PubMed: 34777286
DOI: 10.3389/fmicb.2021.739684 -
Hematology/oncology Clinics of North... Apr 2017Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell malignancies associated with exceptionally poor prognoses. Currently, chemotherapy remains... (Review)
Review
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell malignancies associated with exceptionally poor prognoses. Currently, chemotherapy remains the standard of care, but outcomes are suboptimal, with 5-year survival rates ranging from 15% to 25%. In recent years, several novel agents, including pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have been approved for the treatment of relapsed/refractory PTCL. In addition, numerous other therapies with different mechanisms of action and targets are currently under investigation. This article discusses in detail agents currently available, those currently under investigation, and active combination trials.
Topics: Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Clinical Trials as Topic; Depsipeptides; Disease-Free Survival; Hydroxamic Acids; Immunoconjugates; Lymphoma, T-Cell, Peripheral; Sulfonamides; Survival Rate
PubMed: 28340883
DOI: 10.1016/j.hoc.2016.11.002 -
Oncology (Williston Park, N.Y.) Aug 2015Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma... (Review)
Review
Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma (NHL). Despite the many subtypes now recognized, PTCL represents only approximately 10% of all NHL cases diagnosed. Positron emission tomography/computed tomography has become essential to accurate staging and response-evaluation for PTCL. In comparison to aggressive B-cell NHL, patients with PTCL will more often be refractory to initial therapy, and chemosensitive patients will have shorter disease-free periods. Anthracycline-based regimens, often with the inclusion of etoposide, are commonly used during induction therapy. Consolidation with high-dose therapy and autologous stem cell transplantation (ASCT) in first chemosensitive remission appears to provide the best outcome in common nodal PTCL subtypes. The commonly defined nodal subtypes are PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-positive or ALK-negative anaplastic large-cell lymphoma (ALCL). Four agents have been approved by the US Food and Drug Administration for use in the relapsed/refractory (rel/ref) setting, including belinostat (2014), romidepsin (2011), brentuximab vedotin (2011), and pralatrexate (2009). Brentuximab vedotin was approved only for the ALCL subtype. These agents continue to be studied as combinations in the rel/ref setting and as additions or substitutions for other agents in upfront multiagent chemotherapy regimens. Patients who have responded to treatment in the rel/ref setting and are considered transplant-eligible should be considered for allogeneic stem cell transplantation, especially those with previous ASCT. Upfront allogeneic stem cell transplantation remains a research question in the majority of PTCL subtypes, but data are emerging.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Peripheral; Transplantation, Homologous
PubMed: 26281838
DOI: No ID Found -
Indian Journal of Pharmacology 2022Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing...
Virtual screening and molecular dynamics simulation study of approved drugs as a binder to the linoleic acid binding site on spike protein of SARS-CoV-2 and double mutant (E484Q and L452R).
INTRODUCTION
Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug Administration-approved drugs as binder to the LA binding pocket in wild and double mutant spike protein.
MATERIALS AND METHODS
Approved drugs from DrugBank database (n = 2456) were prepared using Ligprep module of Schrodinger. Crystal structure of LA bound to spike trimer was retrieved (PDB: 6ZB4) and prepared using protein preparation wizard and grid was generated. A virtual screening was performed. With the help of molecular dynamics (MD) studies interaction profile of screened drugs were further evaluated. The selected hits were further evaluated for binding to the double mutant form of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
RESULTS AND DISCUSSION
Following virtual screening, a total of 26 molecules were shortlisted, which were further evaluated using 1ns MD simulation study. Four ligands showing better root mean square deviation (RMSD), RMSD to LA with interaction profile similar to LA were further evaluated using 100 ns MD simulation studies. A total of 2 hits were identified, which performed better than LA (selexipag and pralatrexate). Both these ligands were also found to bind to LA binding site of the double mutant form (E484Q and L452R); however, the binding affinity of pralatrexate was found to be better.
CONCLUSION
We have identified 2 ligands (selexipag and pralatrexate) as possible stable binders to the LA binding site in spike trimer (wild and mutant form). Among them, pralatrexate has shown in vitro activity against SARS-CoV-2, validating our study results.
Topics: Binding Sites; Ligands; Linoleic Acid; Molecular Dynamics Simulation; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Antiviral Agents
PubMed: 36722555
DOI: 10.4103/ijp.ijp_111_22