Molecular studies were performed in axitinib (VEGFR inhibitor)-treated human aortic endothelial cells, and vascular studies were undertaken in isolated intact vessels from mice...This was accompanied by increased p53 acetylation; these effects were mitigated by olaparib or the SIRT1 activator SRT1720...In conclusion, inhibition of VEGFR signalling induces oxidative stress and PARP activation, leading to SIRT1 downregulation, endothelial dysfunction and vascular inflammation. Targeting PARP activation or enhancing SIRT1 activity might represent promising strategies to mitigate VEGF inhibitor-induced vascular complications.

Molecular docking revealed that compound BIT (hybrid in which ketone group of isatin clubbed with thiosemicarbazide) exhibited a docking score of -10.2 kcal/mol, surpassing the binding affinities of the reference ligands axitinib and sorafenib, highlighting its promising potential. The BIT compound was evaluated, and the results indicated that it exhibited significant inhibitory activity against MCF-7 cells at a concentration of 30 mM.

P2, N=29, Active, not recruiting, Tianjin Medical University Cancer Institute and Hospital | Trial completion date: May 2026 --> Dec 2026

P2, N=47, Active, not recruiting, Sun Yat-sen University | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

P2, N=6, Terminated, Changhai Hospital | N=100 --> 6 | Trial completion date: Nov 2026 --> Jun 2026 | Not yet recruiting --> Terminated | Trial primary completion date: Nov 2026 --> Jun 2026; This investigator-initiated study closed to recruitment early due to slower-than-anticipated patient accrual.

P=N/A, N=110, Not yet recruiting, Takeda

P2, N=80, Not yet recruiting, Jiangsu Cancer Institute & Hospital

Recent clinical trials (Axi-STS, TAPPAS) demonstrated that single-agent anti-angiogenic inhibitors (axitinib, pazopanib) achieve modest efficacy (median progression-free survival (PFS) 3.0-4.3 months, response rates 5-13%), underscoring angiosarcoma's complex, multipathway-driven pathogenesis. Environmental exposures (vinyl chloride, thorotrast, radiation) drive distinct angiosarcoma subtypes with subtype-specific mutational profiles. We propose that precision-medicine approaches integrating molecular stratification, pathway crosstalk analysis, and biomarker-guided combination therapies represent the rational next steps to overcome therapeutic resistance and improve clinical outcomes in this lethal malignancy.

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.

These results support a role for VEGF signaling and macrophage-mediated microenvironmental changes in edema and cystic growth of NF2-SWN SE. The observed clinical response to AXITINIB in an index patient suggests that new combinations of anti-angiogenic therapies may represent a promising early targeted approach.

P3, N=136, Not yet recruiting, Shanghai Runshi Pharmaceutical Technology Co., Ltd

P2, N=90, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> May 2027