fingolimod

P3, N=194, Not yet recruiting, Celgene | Initiation date: Jul 2024 --> Nov 2024

Here, we unveil the clinical relevance of SPHK1 in bladder cancer progression and the driver role in bladder cancer metastasis. Moreover, we demonstrated the inhibitory effect of FDA-approved SPHK1 inhibitor FTY720 on bladder cancer metastasis from both in vitro and in vivo models.

Fingolimod was found to reduce ischemic brain injury in a dose-dependent manner. Moreover, it was also found to alleviate inflammation following ischemic brain injury via the HMGB1/TLR4/NF‑κB signaling pathway.

P=N/A, N=30, Completed, Hikma Pharmaceuticals LLC | Active, not recruiting --> Completed | Trial completion date: May 2024 --> Nov 2023

Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.

P4, N=800, Active, not recruiting, The Cleveland Clinic | Trial primary completion date: Apr 2030 --> Jul 2027

Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke...In the future, a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells, along with the activation of M2-type microglia. These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.

P1, N=28, Completed, Wake Forest University Health Sciences | Active, not recruiting --> Completed

P3, N=120, Recruiting, Novartis Pharmaceuticals | N=180 --> 120

P4, N=30, Recruiting, Novartis Pharmaceuticals | Trial completion date: Feb 2025 --> Jan 2026 | Trial primary completion date: Feb 2025 --> Jan 2026

P2, N=38, Not yet recruiting, Medical University of South Carolina

P3, N=194, Not yet recruiting, Celgene

P4, N=800, Active, not recruiting, The Cleveland Clinic | Recruiting --> Active, not recruiting

P3, N=180, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2029 --> Dec 2031 | Trial primary completion date: Aug 2026 --> Mar 2027

P=N/A, N=30, Active, not recruiting, Hikma Pharmaceuticals LLC | Trial completion date: Oct 2023 --> May 2024

Last, analyses of proteomic databases of MS samples identified Ana peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high disease activity. A role for Ana in MS as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and innate remyelination potential in the MS brain.

At present, a series of FTY720 derivatives, which have pharmacological effects such as anti-tumor and alleviating airway hyperresponsiveness, have been developed through structural modification. This article reviews the pharmacological effects of FTY720 and its derivatives.

P1, N=28, Active, not recruiting, Wake Forest University Health Sciences | Recruiting --> Active, not recruiting | N=10 --> 28 | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2023

P3, N=233, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2025 --> Sep 2029

P=N/A, N=1178, Recruiting, Biogen | N=825 --> 1178

These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation.

CM2-II-173 exhibited a more potent effect on the invasiveness of MDA-MB-231 TNBC cells compared to FTY720. Taken together, this study demonstrated that CM2-II-173 has the potential to be a lead compound that can inhibit cancer progression of not only TNBC cells, but also of liver, prostate, and ovarian cancer cells.

Fingolimod can promote the arrest in G0/G1 of SCC9 cells, and PLK1 is a key targeted gene for the treatment of HNSC. Fingolimod can inhibit cell proliferation caused by PLK1 over-expression.

Mice were divided into six groups: Sham, TAC, Sham+RAGE-/-, TAC+RAGE-/-, AG, and FTY720 group...Deficient of AGEs, RAGE and activating PP2A can significantly attenuate the cognitive impairment in CHF mice, and protect the brain structure. This mechanism seems via reducing the expression of Aβ, p-tau, and apoptotic protein.

P1, N=2, Completed, Mayo Clinic | Active, not recruiting --> Completed

There are a few reports of melanoma as a side effect of Fingolimod in the literature. Herein we aim to report a known case of multiple sclerosis under Fingolimod presenting with persistent nasal congestion who was eventually diagnosed with soft palate malignant melanoma.

These neuroinflammatory events were induced by TRMs, as depletion of peripheral T cells or blocking T cell trafficking using FTY720 did not change the neuroinflammatory course...The use of cognate antigen to reactivate CD8 TRMs enables us to isolate the neuropathologic effects induced by this cell type independently of other immune cells, differentiating this work from studies employing whole pathogen re-challenge. This study also demonstrates the capacity for CD8 TRMs to contribute to pathology associated with neurodegenerative disorders and long-term complications associated with viral infections.

Furthermore, the intratumoral effector memory T cells (Tem), CD45, CD3, CD8, CD44, and CD62L, did not decrease after blocking the egress of T cells from tumor-draining lymph nodes by FTY-720. These results demonstrated that the nanovaccine can foster TLS formation, which thus enhances local immune responses significantly, delays tumor outgrowth, and prolongs the median survival time of murine models of mimicry nasopharyngeal carcinoma, demonstrating a promising strategy for nanovaccine development.

By using FTY720 to inhibit T-cell circulation upon tumor challenge, we confirmed that TRM are crucial contributors to the vaccine efficacy. In conclusion, induction of tumor-antigen specific lung TRM are a key point in local protection against pulmonary metastasis. Ongoing studies analyze the therapeutic use of this vaccination strategy as well as its potential in combination with immune checkpoint inhibition.

Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared with empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death...Combined dasatinib and M3814 treatment also synergistically inhibited phosphorylation of the transcriptional regulators MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising therapeutic target for KIT mutant cancers.

BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier...As a result, the co-delivery of heat shock protein 70 inhibitor VER-155008 with ZnCoFe NCs could realize synergistic magnetic hyperthermia effects upon exposure to an alternating current magnetic field (ACMF) in both GL261 and U87 brain tumor models. This modulation approach brings new ideas for the treatment of central nervous system diseases that require delivery of therapeutic agents across the blood-brain barrier (BBB).

In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [Ga]Ga-DOTA-PEG-TZ(PEG-Octr)-PEG-Trz-PEG-Val-Cit-pABOC-FTY720 in SSTR2 prostate cancer xenografts than in the SSTR2 xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC.

D2C7-IT+αCD40 treatment stimulated intratumoral CD8 T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.

iVEC transplantation suppresses neuroinflammation, but suppression of neuroinflammation per se does not promote remyelination. Recruitment of Tregs by transplanted iVECs contributes significantly to promotion of remyelination in the injured white matter.

Studies on the effect of quercetin and fingolimod on the two proteins associated with apoptotic events, AKT and Bcl-2, showed that only quercetin, alone or in combination, down-regulated the activity of the two proteins. The reported observations provide information which can be useful in the search of novel anti-tumor approaches, aiming at optimization of the therapeutic effect and maximal preservation of healthy tissues.

The PP2A activator FTY720 reduced levels of phosphorylated stathmin. Eribulin-resistant leiomyosarcoma cell lines had enhanced expression of the class Ⅰ β-tubulin TUBB1, multi-drug resistance 1 protein MDR1 and breast cancer-resistance protein BCRP, and decreased expression of stathmin. Taken together, these results suggest that stathmin expression modulates the pharmacological efficacy of eribulin in uterine leiomyosarcoma cells.