S1P signaling was pharmacologically inhibited using the FDA-approved S1P modulator FTY720 (Fingolimod)...These findings identify a previously unrecognized acidosis-S1P axis that contributes to angiogenic remodeling in osteosarcoma. Our results highlight the multifaceted role of S1P in regulating endothelial behavior and suggest that targeting S1P signaling may represent a promising strategy to disrupt pathological neoangiogenesis in osteosarcoma.

Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70 S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy.

The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors.

Effective PD-1 blockade in bladder cancer significantly depends on intact tdLNs and active lymphocyte trafficking. Preserving nodal integrity may optimize immunotherapy responses, supporting the rationale the rationale for neoadjuvant PD-1 blockade prior surgical disruption of lymphatic channels.

P2, N=15, Active, not recruiting, Viatris Pharmaceuticals Co., Ltd. | Enrolling by invitation --> Active, not recruiting

P1, N=6, Completed, Viatris Innovation GmbH | Recruiting --> Completed

FTY720, a compound known to restore PP2A phosphatase activity, inhibited tumor sphere formation by mouse and human neurofibroma Schwann cell progenitor cells, suppressed the proliferation of both primary and immortalized neurofibroma-derived Schwann cells, and induced cell apoptosis in vitro. Furthermore, treatment with FTY720-alone or in combination with MEKi-significantly suppressed tumor number and reduced tumor burden in remaining tumors in a murine model of NF1, highlighting the promise of using FTY720 as a novel therapeutic strategy in NF1.

Similarly, the administration of the S1PR1 antagonist FTY720 also alleviated bone loss in the breast cancer-bearing mice fed a high-fat diet. These studies indicate that genetic silencing and pharmacological inhibition can suppress S1P-dependent bone loss in doxorubicin-induced obese breast cancer mice. S1P shows promise as a potential drug target for preventing chemotherapy-induced bone loss in patients.

P2, N=213, Terminated, Oppilan Pharma Ltd | The Sponsor decided to terminate clinical conduct in the Open-Label Extension Period. The decision to terminate the study was not due to safety concerns.

P3, N=470, Active, not recruiting, Viatris Innovation GmbH | Recruiting --> Active, not recruiting

Building on our work with the structurally related compound KRP203, we show that high-dose FTY720 produces isozyme-divergent modulation across phosphoinositide kinases and biases PIKFYVE activity toward phosphatidylinositol, a pattern we term ASURA (Asymmetric Simultaneous Uncoupling of Related Activities). Patient-derived glioblastoma (GBM) neurospheres were sensitive to FTY720, and co-treatment with a PI3Kα-selective inhibitor augmented growth suppression in U87MG cells. Together, these data support a model in which ASURA-dose FTY720 disrupts phosphoinositide-regulated trafficking and nutrient access, imposing intracellular nutrient stress that culminates in tumor-cell death.

P1, N=6, Completed, Viatris Innovation GmbH | Active, not recruiting --> Completed