-
International Journal of Dermatology Apr 2023
Topics: Humans; Sezary Syndrome; Electrons; Hematopoietic Stem Cell Transplantation; Skin Neoplasms; Mycosis Fungoides
PubMed: 36683181
DOI: 10.1111/ijd.16587 -
Annals of Translational Medicine Jul 2022Multiple myeloma (MM) with t (11;14) has a unique biology. New combinations of novel agents are needed to improve the prognosis of patients with t (11;14) MM. As a...
BACKGROUND
Multiple myeloma (MM) with t (11;14) has a unique biology. New combinations of novel agents are needed to improve the prognosis of patients with t (11;14) MM. As a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), palbociclib (PAL) has been used to treat various malignancies, including breast cancer, ovarian cancer, and so on. However, the effects of PAL on MM remain unclear, and thus, further investigations are warranted.
METHODS
Two t (11;14) MM cell lines, U266 and KMS27, were used in this study. The cell viability and cell cycle were detected to evaluate the anti-myeloma effect of the combination of pralatrexate (PTX) and methotrexate (MTX) with PAL. Three-dimensional (3D) spheroid and mouse models were built to verify the effect of the combination treatment. Western blot was used to detect the expressions of Minichromosome Maintenance Complex Component 2 (MCM2), Minichromosome Maintenance Complex Component 3 (MCM3), and dihydrofolate reductase (DHFR).
RESULTS
It was observed that PAL had obvious anticancer effects on U266 and KMS27 cells, which had synergistic effects together with PTX and MTX. Importantly, it was found that PAL could promote cell cycle genes including MCM2 and MCM3, and increase the number of MM cells in the G1 phase. Moreover, PAL reduced the expression level of DHFR and exerted its anticancer effects on MM cells by targeting DHFR. It was also determined that PAL exerted anticancer effects on MM in the spheroid and mouse models.
CONCLUSIONS
PAL exerted obvious anticancer effects on t (11;14) MM cells, which had synergistic effects together with PTX and MTX. PAL could promote cell cycle genes and the G1 phase of MM cells. Moreover, PAL reduced the expression level of DHFR and exerted its anticancer effects on t (11;14) MM cells by targeting DHFR.
PubMed: 35957711
DOI: 10.21037/atm-22-2830 -
Cancer Treatment and Research 2015Peripheral T-cell lymphomas (PTCLs) are an uncommon group of lymphoproliferative disorders accounting for approximately 10-15 % of all non-Hodgkin lymphomas (NHL) in... (Review)
Review
Peripheral T-cell lymphomas (PTCLs) are an uncommon group of lymphoproliferative disorders accounting for approximately 10-15 % of all non-Hodgkin lymphomas (NHL) in Western countries. Although PTCLs are associated with poor prognosis, outcomes vary with disease subtype. The standard of care has been anthracycline-based induction combination chemotherapy, however, with the exception of low-risk ALK-positive anaplastic large cell lymphoma, relapse rates are high. Therefore, consolidation with autologous stem cell transplantation is usually recommended for patients deemed candidates, and with aggressive subtypes. In recent years, a number of novel agents including pralatrexate, histone deacetylase inhibitors, immunotoxins, proteasome inhibitors, aurora kinase inhibitors and the CD30 antibody-drug conjugate brentuximab vedotin, have shown promise in the treatment of PTCLs. Studies are underway to explore the activity of these newer agents used in the frontline setting.
Topics: Aminopterin; Antineoplastic Agents; Brentuximab Vedotin; Diphtheria Toxin; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lymphoma, T-Cell, Peripheral; Molecular Targeted Therapy; Protein Kinase Inhibitors; Recombinant Fusion Proteins; Stem Cell Transplantation
PubMed: 25655615
DOI: 10.1007/978-3-319-13150-4_12 -
Seminars in Hematology Apr 2021Peripheral T-cell lymphomas (PTCL) are rare lymphoproliferative disorders with poor outcomes and high rates of relapse. Incidence varies although the most common...
Peripheral T-cell lymphomas (PTCL) are rare lymphoproliferative disorders with poor outcomes and high rates of relapse. Incidence varies although the most common subtypes include PTCL-not-otherwise specified, anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma. Anaplastic large cell lymphoma is characterized by near-universal CD30 expression and serves as a prototypic model for other CD30-expressing lymphomas. Historically, these neoplasms have been treated with regimens used in the treatment of aggressive B-cell lymphomas. Over the last decade, brentuximab vedotin, an antibody-drug conjugate, has been investigated to treat peripheral T-cell lymphomas expressing CD30. While first studied in the relapsed and refractory setting, it was later studied in the frontline setting in the ECHELON-2 trial with positive results and is now an approved treatment for CD30-expressing peripheral T-cell lymphomas. Other treatment options in the relapsed and refractory setting include histone deacetylase inhibitors, pralatrexate, and salvage multiagent chemotherapy regimens. Current research is underway regarding combination therapies and the use of other novel agents.
Topics: Brentuximab Vedotin; Humans; Immunoconjugates; Ki-1 Antigen; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local
PubMed: 33906726
DOI: 10.1053/j.seminhematol.2021.02.006 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2018Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T-cell lymphoma (CD8 PCAETL) is a rare subtype of peripheral T-cell lymphoma with poor outcomes and...
BACKGROUND
Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T-cell lymphoma (CD8 PCAETL) is a rare subtype of peripheral T-cell lymphoma with poor outcomes and without a standardized treatment strategy. Allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy.
PATIENTS AND METHODS
We conducted a retrospective case series. We identified 8 patients with the diagnosis of CD8 PCAETL, 4 of whom also underwent allogeneic HSCT.
RESULTS
Eight patients were treated at our center with combination chemotherapy and several novel agents, including histone deacetylase inhibitors, brentuximab, and pralatrexate. Patients underwent a median of 8.5 treatments before HSCT. Six of the 8 patients examined, including all 4 who received an HSCT, were alive at their last follow-up.
CONCLUSION
Allogeneic HSCT is a promising treatment modality for CD8 PCAETL. Because of the aggressive nature of this disease and lack of sustained remission with currently available therapies, HSCT should be considered early in the course of treatment. Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8 PCAETL, and may be incorporated earlier in the treatment course.
Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Retrospective Studies; Transplantation Conditioning; Treatment Outcome; Young Adult
PubMed: 29223388
DOI: 10.1016/j.clml.2017.11.004 -
PLoS Computational Biology Dec 2020The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No...
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008μM and 9.453 μM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.
Topics: Aminopterin; Animals; Antiviral Agents; Azithromycin; Chlorocebus aethiops; Computer Simulation; Deep Learning; Drug Evaluation, Preclinical; Drug Repositioning; Molecular Dynamics Simulation; RNA-Dependent RNA Polymerase; SARS-CoV-2; Vero Cells; Virus Replication; COVID-19 Drug Treatment
PubMed: 33382685
DOI: 10.1371/journal.pcbi.1008489 -
Leukemia & Lymphoma Sep 2020Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to...
Angioimmunoblastic T-cell lymphoma (AITL) is a histological subtype of peripheral T-cell lymphoma associated with a poor prognosis. This post-hoc pooled analysis aims to provide insight about the efficacy of pralatrexate monotherapy in a subset of twenty-nine patients with relapsed or refractory (r/r) AITL drawn from two prospective registration trials completed in China and Japan. After a median of two prior lines of therapy, an overall response rate of 52% (15/29 patients; 95% CI 0.34, 0.70) was demonstrated. The estimated median duration of response, progression free survival (PFS) and overall survival (OS) were 6.4 months (196 days), 5.0 months (151 days), and 18.0 months (548 days), respectively. Grades 1-3 mucositis was observed in twenty-three patients (79.3%); and hemato-toxicity in twenty-six (89.7%) patients. Results of this analysis corroborate with data from two previously reported US retrospective cohorts, supporting the potential benefits of pralatrexate monotherapy in patients with r/r AITL.
Topics: Aminopterin; China; Humans; Japan; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Prospective Studies; Retrospective Studies
PubMed: 32536233
DOI: 10.1080/10428194.2020.1765232 -
Oncotarget May 2020Multiple myeloma (MM) is the second most common hematologic malignancy. While major advances have been made in the disease, it is still incurable. Although...
Multiple myeloma (MM) is the second most common hematologic malignancy. While major advances have been made in the disease, it is still incurable. Although antifolate-based drugs are not commonly used to treat myeloma, new generation analogs with distinct patterns of preclinical and clinical activity may offer an opportunity to identify new classes of potentially active drugs. Pralatrexate (PDX), which was approved for the treatment of relapsed or refractory peripheral T-cell lymphoma in 2009, may be one such drug. Pralatrexate exhibits a potency and pattern of activity distinct from its predecessors like methotrexate (MTX). We sought to understand the activity and mechanisms of resistance of multiple myeloma to these drugs, which could also offer potential strategies for selective use of the drug. We demonstrate that PDX and MTX both induce a significant decrease in cell viability in the low nanomolar range, with PDX exhibiting a more potent effect. We identified a series of myeloma cell lines exhibiting markedly different patterns of sensitivity to the drugs, with some lines frankly resistant, and others exquisitely sensitive. These differences were largely attributed to the basal RFC (Reduced Folate Carrier) mRNA expression levels. RFC mRNA expression correlated directly with rates of drug uptake, with the most sensitive lines exhibiting the most significant intracellular accumulation of pralatrexate. This mechanism explains the widely varying patterns of sensitivity and resistance to pralatrexate in multiple myeloma cell lines. These findings could have implications for this class of drugs and their role in the treatment of multiple myeloma.
PubMed: 32405334
DOI: 10.18632/oncotarget.27516 -
The Journal of Clinical Endocrinology... Sep 2021Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF...
BACKGROUND
Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development.
MATERIAL AND METHODS
Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents.
RESULTS
Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53.
CONCLUSIONS
HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
Topics: Animals; Antineoplastic Agents; Carcinogenicity Tests; Cell Line, Tumor; Disease Models, Animal; High-Throughput Screening Assays; Humans; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Microenvironment
PubMed: 34120183
DOI: 10.1210/clinem/dgab424 -
Internal Medicine Journal Oct 2022Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes...
Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.
Topics: Humans; Lymphoma, T-Cell, Peripheral; Vincristine; Brentuximab Vedotin; Prednisone; Consensus; Follow-Up Studies; Antineoplastic Combined Chemotherapy Protocols; Australia; Cyclophosphamide; Doxorubicin; Biomarkers
PubMed: 34668281
DOI: 10.1111/imj.15595