Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models.
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SUBMITTER: Rupp T
PROVIDER: S-EPMC9330228 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Surgery followed by a chemotherapy agent is the first-line treatment for breast cancer patients. Nevertheless, new targets are required for women with triple-negative breast cancer (TNBC) in order to improve the treatment of this aggressive cancer subtype. Multiple pro-inflammatory molecules including lipid-based substances such as sphingosine-1-phosphate (S1P) promote cancer progression. In this preclinical study, we aim to investigate the efficacy of Fingolimod, an inhibitor of S1P / S1P receptors axis, already approved as an immunomodulator in multiple sclerosis. The impact of Fingolimod was analyzed using in vitro 2D and 3D cell survival analysis and in vivo orthotopic graft models, using mouse and human TNBC cells implanted in immunocompetent or immunodeficient mice, respectively. Resection of the tumor primary mass was also performed to mimic the clinical standard of care. We demonstrated that Fingolimod repressed tumor cell survival in vitro. We also showed in preclinical mouse TNBC models that Fingolimod repressed tumor progression and liver and spleen metastases without apparent adverse effects on the animals. Our data indicate that Fingolimod induces tumor cells apoptosis and thereby represses tumor progression. Globally, our data suggest that Fingolimod merits further evaluation as a potential therapeutic opportunity for TNBC.
| S-EPMC7649527 | biostudies-literature
Project description:ObjectiveTo compare 2-year effectiveness and discontinuation of natalizumab (NTZ) versus fingolimod (FTY) and dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS).MethodsPatients prescribed NTZ, FTY, or DMF at the Rocky Mountain MS Center at University of Colorado were identified. Clinician-reported data were retrospectively collected. Outcomes include a composite effectiveness measure consisting of new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse, individual effectiveness outcomes and discontinuation over 2 years. Logistic regression was used for data analysis on patients matched by propensity scores and using ATT doubly robust weighting estimator.ResultsA total of 451, 271, and 342 patients were evaluated on NTZ, FTY, and DMF over 2 years, respectively. Patients had a mean age of 39.8 (NTZ), 42.5(FTY), and 45.8 (DMF) years; were predominantly female (76.7% NTZ; 72.0% FTY; 69.6% DMF); and had a mean MS disease duration of 11-12 years for all groups. At ≤24 months, 22.2%, 34.7%, and 33.6% experienced a new T2 lesion, gadolinium-enhancing lesion, and/or clinical relapse on NTZ, FTY, and DMF, respectively. Using ATT doubly robust weighting estimator, FTY versus NTZ and DMF versus NTZ had an odds ratio of 2.00 (95%CI:[1.41-2.85], P < 0.001) and 2.38 [95% CI: 1.68-3.37], P < 0.001) respectively, for experiencing a new T2 lesion, gadolinium enhancing lesion, and/or clinical relapse. At ≤24 months, 32.6%, 34.3%, and 47.1% discontinued NTZ, FTY, and DMF, respectively. The majority of discontinuations were due to becoming JCV positive(12.6%) for NTZ and due to adverse events for both FTY(17%) and DMF(24.0%).InterpretationNTZ appears to be more effective and tolerable than FTY and DMF.
| S-EPMC6389745 | biostudies-literature
Project description:Background: Despite the recent approval of new oral therapies for the treatment of multiple sclerosis (MS), a significant percentage of patients are still not free from disease activity. In view of the complex pathogenesis and the relapsing and progressive nature of MS, combination therapy, a classical approach to treat many chronic diseases, could improve disease control over monotherapy. Ponesimod, a selective and rapidly reversible sphingosine-1-phosphate receptor Type 1 (S1P1) modulator, currently in Phase III clinical trial stage in relapsing MS (RMS), and dimethyl fumarate (DMF) would potentially be an ideal combination due to their differing mechanisms of action and oral administration. Objective: The goal of the study was to evaluate the therapeutic effect of ponesimod monotherapy and investigate the potential additive, or synergistic, activity of ponesimod-DMF combination therapy in experimental autoimmune encephalomyelitis (EAE) animal models of MS. Methods: Efficacy was evaluated in the myelin oligodendrocyte glycoprotein (MOG)-induced EAE model in C57BL/6 mice (ponesimod monotherapy) and in the myelin basic protein (MBP)-induced EAE model in Lewis rats (monotherapies and combination therapy). The principal readout was the clinical score assessing paralysis. Additional readouts, such as histopathology, survival, and disease prevalence, were generated in parallel when applicable. Results: Ponesimod monotherapy in the mouse EAE model showed significant efficacy in both preventative and therapeutic settings. In the rat EAE model, ponesimod demonstrated significant dose-dependent efficacy on clinical scores, while DMF showed only modest activity. Combination therapy synergistically reduced the severity and prevalence of disease. Only the combination treatment of ponesimod and DMF fully suppressed clinical disease activity by the end of the study. Conclusion: The results support the potential therapeutic benefits of combining ponesimod with DMF to improve disease activity control in patients with MS. Additionally, the results suggest that combining ponesimod with other oral agents that have different mechanisms of action might also be therapeutically beneficial to patients with MS.
| S-EPMC6538399 | biostudies-literature
Project description:IntroductionLimited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist.MethodsClinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator.ResultsA total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX.InterpretationRTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.
| S-EPMC7480919 | biostudies-literature
Project description:To evaluate the long-term effects of treatments used in MS on the T-cell trafficking profile.We enrolled 83 patients with MS under fingolimod (FTY), natalizumab (NTZ), dimethyl fumarate (DMF), or other disease-modifying treatments (DMTs). Blood was drawn before treatment onset and up to 36-48 months. The ex vivo expression of CNS-related integrins (?4?1 and ?L subunit of LFA-1) and the gut-related integrin (?4?7) was assessed using flow cytometry on CD4+ and CD8+ T cells. The adhesion profiles of CD3+ T cells to specific integrin ligands (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and mucosal vascular addressin cell adhesion molecule-1 [MAdCAM-1]) were measured in vitro before and after 12 and 36-48 months.NTZ decreased the frequency of ?4?1+ and ?4?7+ integrin expressing T cells and the binding of these cells to VCAM-1 and MAdCAM-1, respectively. After 12 months, DMF induced a decreased frequency of ?LhighCD4+ T cells combined with reduced binding to ICAM-1. By contrast, with FTY, there was a doubling of the frequency of ?4?1+ and ?Lhigh, but a decreased frequency of ?4?7+ T cells. Strikingly, the binding of ?4?1+, ?4?7+, and to a lesser extent of ?Lhigh T cells to VCAM-1, MAdCAM-1, and ICAM-1, respectively, was decreased at month 12 under FTY treatment. The presence of manganese partially restored the binding of these T cells to VCAM-1 in vitro, suggesting that FTY interferes with integrin activation.In addition to NTZ, DMF and FTY but not other tested DMTs may also decrease T-cell-mediated immune surveillance of the CNS. Whether this mechanism may contribute to the onset of CNS opportunistic infections remains to be shown.
| S-EPMC5639463 | biostudies-literature
Project description:BackgroundDimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple sclerosis (RRMS).ObjectiveTo compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.MethodsWe identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.ResultsOf the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8-1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6-1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6-1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.ConclusionDimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.
| S-EPMC7914245 | biostudies-literature
Project description:BackgroundPatients with Multiple Sclerosis (PwMS) display altered lipoproteins levels and function, which seem to affect disease risk and progress. Whether disease-modifying therapies affect the lipoprotein profile in PwMS has scarcely been studied.ObjectiveThe study aims to assess whether fingolimod and dimethyl fumarate (DMF) affect lipoproteins in PwMS.MethodsWe compared retrospectively the blood lipoprotein levels of 29 fingolimod-treated and 41 DMF-treated patients before and after 3 and 12 months of therapy. Patients treated with cholesterol-reducing medications were not included. Data on weight change and disease activity during 1-year follow-up were obtained.ResultsHDL level, HDL/LDL ratio and HDL/total cholesterol ratio were increased in both treatment groups after 3 months' therapy and sustained, with no change in LDL or triglycerides. While at baseline only 26% of patients met the recommended minimum of HDL 60 mg/dl, after 3 months' therapy, 43% of fingolimod-treated and 47% of DMF-treated patients reached the recommended level. The majority of patients had no weight reduction.ConclusionsFingolimod and DMF therapies are associated with a specific increase in HDL in PwMS. Further studies are required to validate these findings and their potential implication as biomarker of reduced inflammatory state and/or reduced risk of neurodegeneration or cardiovascular comorbidity.
| S-EPMC6794658 | biostudies-literature
Project description:ImportanceAs disease-modifying treatment options for multiple sclerosis increase, comparisons of the options based on real-world evidence may guide clinical decision-making.ObjectiveTo compare the relapse outcomes between 2 pairs of disease-modifying treatments: dimethyl fumarate vs fingolimod and natalizumab vs rituximab.Design, setting, and participantsThis comparative effectiveness study integrated data from a clinic-based multiple sclerosis research registry and its linked electronic health records (EHR) system between January 1, 2006, and December 31, 2016, and built treatment groups for each pairwise disease-modifying treatment comparison according to both registry records and electronic prescriptions. Parallel analyses were conducted from October 11, 2019, to July 7, 2021.Main outcomes and measuresThe main outcomes were the 1-year and 2-year relapse rates as well as the time to relapse. To compare relapse outcomes, the study adjusted for covariates from 2 sources (registry and EHR) and corrected for confounding biases among the covariates by the doubly robust estimation.ResultsThe study included 4 treatment groups: dimethyl fumarate (n = 260; 198 women [76.2%]; 227 non-Hispanic White individuals [87.3%]; mean [SD] age at diagnosis, 41.7 [10.4] years), fingolimod (n = 267; 190 women [71.2%]; 222 non-Hispanic White individuals [83.1%]; mean [SD] age at diagnosis, 37.9 [9.9] years), natalizumab (n = 204; 160 women [78.4%]; 172 non-Hispanic White individuals [84.3%]; mean [SD] age at diagnosis, 37.2 [10.6] years), and rituximab (n = 115; 83 women [72.2%]; 99 non-Hispanic White individuals [86.1%]; mean [SD] age at diagnosis, 44.1 [11.1] years). No significant differences were found in the relapse outcomes between dimethyl fumarate and fingolimod after correcting for confounding biases and multiple testing (difference in 1-year relapse rate, 0.028 [95% CI, -0.031 to 0.084]; difference in 2-year relapse rate, 0.071 [95% CI, 0.008-0.128]; relative risk of 2-year non-relapse, 0.957 [95% CI, 0.884-1.035] with dimethyl fumarate as reference). When compared with rituximab, natalizumab was associated with a higher relapse rate for all 3 outcomes after bias correction and multiple testing (difference in 1-year relapse rate, 0.080 [95% CI, 0.013-0.137]; difference in 2-year relapse rate, 0.132 [95% CI, 0.043-0.189]; relative risk of 2-year non-relapse, 0.903 [95% CI, 0.822-0.944]). Confounders were identified from EHR data not recorded in the registry data through data-driven feature selection.Conclusions and relevanceThis study reports real-world evidence of equivalent relapse outcomes between dimethyl fumarate and fingolimod and relapse reduction in favor of rituximab relative to natalizumab. This approach illustrates the value of incorporating EHR data as high-dimensional covariates in real-world treatment comparison.
| S-EPMC8596196 | biostudies-literature
Project description:BackgroundFingolimod (FTY) and dimethyl fumarate (DMF) are multiple sclerosis (MS) oral therapies that became available in 2010 and 2013, respectively.ObjectiveThe objective of this article is to compare discontinuation rates, efficacy, and adverse events (AEs) of FTY and DMF over two years.MethodsPatients prescribed FTY or DMF at the Rocky Mountain MS Center at University of Colorado prior to October 2013 were identified. Clinician-reported data were retrospectively collected. Primary outcome was discontinuation of drug by the end of year two. Reasons for discontinuation were evaluated.ResultsA total of 271 FTY and 342 DMF patients were evaluated. Patients had a mean age of 42.5 (FTY) and 45.8 (DMF) years and were predominantly female (72.0% FTY; 69.6% DMF) and white (86.3% FTY; 82.2% DMF). At ≤24 months, 93 (34.3%) and 161 (47.1%) discontinued FTY and DMF, respectively, with an unadjusted odds ratio (OR) of 1.70 (1.23-2.37, p = 0.002), or 1.69 (1.16-2.46, p = 0.006) for the doubly robust propensity score weighted estimator. Primary reason for discontinuation was AEs, which were less likely for FTY 46 (17.0%) compared to DMF 82 (24.0%) (OR 1.54, 1.03-2.31, p = 0.035). Discontinuation due to disease activity (FTY (10%) DMF (11.1%); OR 1.13, 0.67-1.90, p = 0.647) and breakthrough disease activity, regardless of discontinuation (FTY (34.7%) DMF (33.6%); OR 0.95, 0.68-1.34, p = 0.783), were similar.ConclusionsThe odds of discontinuation were less for FTY than DMF, and were driven by AEs for both drugs.
| S-EPMC5564884 | biostudies-literature
Project description:Since we first reported the antitumor efficacy of IL-27 in 2004, accumulating evidence obtained by several groups using a variety of preclinical mouse models indicates that IL-27 possesses potent antitumor activity against various types of tumors through multiple mechanisms depending on the characteristics of individual tumors without apparent adverse effects.
| S-EPMC4589049 | biostudies-other