Search

Background: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMTs) for relapsing multiple sclerosis (MS). There are currently no known head-to-head studies comparing DMF and FTY over 36 months, which leaves their relative effectiveness unknown., Objective: To assess real-world discontinuation, effectiveness, and switching practices of DMF and FTY over 36 months along with disease activity after switching DMT., Methods: Patients prescribed DMF (n = 737) and FTY (n = 535) from two academic MS centers were retrospectively reviewed. Discontinuation and effectiveness outcomes were assessed using propensity score (PS) weighting. PS model covariates included sociodemographics and clinical and MRI characteristics., Results: Discontinuation was more common in DMF (58.3%) versus FTY (45.2%) over 36 months [OR = 1.81, 95% CI (1.41-2.31), p < .001], largely driven by intolerance [OR = 1.63, 95% CI (1.18-1.73), p < .001]. There were no differences in clinical relapses [OR = 1.27, 95% CI (0.90-1.79), p = .17], gadolinium-enhancing (GdE) lesions [OR = 1.25, 95% CI (0.85-1.84), p = .26], or new T2-hyperintense lesions [OR = 0.99, 95% CI (0.74-1.32), p = .93]. Within 12 months of DMF/FTY discontinuation, switchers to highly effective therapy (HET) versus other DMTs (injectables/orals) had fewer relapses (DMF/HET, 5.9% versus DMF/Other, 14.2%, p = .03; FTY/HET, 11.6% versus FTY/Other, 18.0%, p = .04) and fewer GdE lesions post-FTY (DMF/HET, 10.3% versus DMF/Other, 14.3%, p = .36; FTY/HET, 11.9% versus FTY/Other, 21.5%, p = .04)., Conclusion: This combined analysis showed similar effectiveness for DMF and FTY over 36 months with higher DMF discontinuations. Disease activity was lower in switchers to HET versus injectable/oral therapies after DMF/FTY cessation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Previously we demonstrated that the multiple sclerosis drug dimethyl fumarate (DMF) and its plasma breakdown product MMF could interact with chemotherapeutic agents to kill both GBM cells and activated microglia. The trial NCT02337426 demonstrated the safety of DMF in newly diagnosed GBM patients when combined with the standard of care Stupp protocol. We hypothesized that another multiple sclerosis drug, fingolimod (FTY720) would synergize with MMF to kill GBM cells. MMF and fingolimod interacted in a greater than additive fashion to kill PDX GBM isolates. MMF and fingolimod radiosensitized glioma cells and enhanced the lethality of temozolomide. Exposure to [MMF + fingolimod] activated an ATM-dependent toxic autophagy pathway, enhanced protective endoplasmic reticulum stress signaling, and inactivated protective PI3K, STAT, and YAP function. The drug combination reduced the expression of protective c-FLIP-s, MCL-1, BCL-XL, and in parallel caused cell-surface clustering of the death receptor CD95. Knock down of CD95 or over-expression of c-FLIP-s or BCL-XL suppressed killing. Fingolimod and MMF interacted in a greater than additive fashion to rapidly enhance reactive oxygen species production and over-expression of either thioredoxin or super-oxide dismutase two significantly reduced the drug-induced phosphorylation of ATM, autophagosome formation and [MMF + fingolimod] lethality. In contrast, the production of ROS was only marginally reduced in cells lacking ATM, CD95, or Beclin1. Collectively, our data demonstrate that the primary generation of ROS by [MMF + fingolimod] plays a key role, via the induction of toxic autophagy and death receptor signaling, in the killing of GBM cells.

Previously we demonstrated that the multiple sclerosis drug dimethyl fumarate (DMF) and its plasma breakdown product MMF could interact with chemotherapeutic agents to kill both GBM cells and activated microglia. The trial NCT02337426 demonstrated the safety of DMF in newly diagnosed GBM patients when combined with the standard of care Stupp protocol. We hypothesized that another multiple sclerosis drug, fingolimod (FTY720) would synergize with MMF to kill GBM cells. MMF and fingolimod interacted in a greater than additive fashion to kill PDX GBM isolates. MMF and fingolimod radiosensitized glioma cells and enhanced the lethality of temozolomide. Exposure to [MMF + fingolimod] activated an ATM-dependent toxic autophagy pathway, enhanced protective endoplasmic reticulum stress signaling, and inactivated protective PI3K, STAT, and YAP function. The drug combination reduced the expression of protective c-FLIP-s, MCL-1, BCL-XL, and in parallel caused cell-surface clustering of the death receptor CD95. Knock down of CD95 or over-expression of c-FLIP-s or BCL-XL suppressed killing. Fingolimod and MMF interacted in a greater than additive fashion to rapidly enhance reactive oxygen species production and over-expression of either thioredoxin or super-oxide dismutase two significantly reduced the drug-induced phosphorylation of ATM, autophagosome formation and [MMF + fingolimod] lethality. In contrast, the production of ROS was only marginally reduced in cells lacking ATM, CD95, or Beclin1. Collectively, our data demonstrate that the primary generation of ROS by [MMF + fingolimod] plays a key role, via the induction of toxic autophagy and death receptor signaling, in the killing of GBM cells. [ABSTRACT FROM AUTHOR]

Keywords: fingolimod; dimethyl fumarate; Gilenya; Tecfidera; RAS; glioblastoma; microglia EN fingolimod dimethyl fumarate Gilenya Tecfidera RAS glioblastoma microglia 1 2 2 05/05/20 20200430 NES 200430 In the original article, there was a mistake in Figure 7C as published. Footnotes 1 Edited and reviewed by: Liam Chen, Johns Hopkins University, United States 2 This article was submitted to Neuro-Oncology and Neurosurgical Oncology, a section of the journal Frontiers in Oncology Fingolimod, dimethyl fumarate, Gilenya, Tecfidera, RAS, glioblastoma, microglia. [Extracted from the article]