linsitinib (ASP7487)

IGFBP5 knockout or treatment with the IGF1R inhibitor OSI-906 enhances CD8+ T cell infiltration and synergizes with anti-PD1 therapy. Furthermore, this ASCL1-IGFBP5-IGF1R axis and the BVG are conserved across multiple neuroendocrine cancers (NECs). Our findings reveal a previously unrecognized vascular gate in NECs and propose novel therapeutic strategies to enhance immunotherapy efficacy in these recalcitrant cancers.

This study identifies PIK3CG, PRKCD, and TRIM22 as potential biomarkers and therapeutic targets in IDH-wildtype GBM. Their paradoxical association with poor survival and immune activation may inform personalized treatment strategies that combine conventional chemotherapy with immune-based therapies. While our findings are robust across both mixed and IDH-wildtype-focused cohorts, further mechanistic validation is warranted.

Targeted and molecular therapies in EWS show significant promise, particularly in rational combinations that exploit the tumor's dependence on EWS-FLI1-driven transcriptional dysregulation, DNA damage repair deficiencies, or survival signaling. Future research must prioritize biomarker-driven patient selection, integration of multiomics approaches, and multicenter prospective trials to translate these strategies into clinically meaningful improvements in EWS survival.

Interestingly, the molecular docking analyses indicated β-sitosterol to have stronger affinity to ERα, ERβ, IGF1R and VEGFR2 than that of their known inhibitors (tamoxifen, diarylpropionitrile, linsitinib and sorafenib, respectively). Finally, molecular dynamics simulations analyses confirmed strong molecular interactions of β-sitosterol with VEGFR2 and ERβ. Taken together, the findings highlight potential of phytoconstituents of Pterospermum acerifolium, especially β-sitosterol, kaempferol and luteolin, for clinical management of breast cancer and its metastasis to the bone.

Besides, patients in the high-risk group exhibited lower IC50 values for vorinostat, elesclomol, OSI-906, pyrimethamine, thapsigargin, and doxorubicin, but a higher IC50 value for cisplatin, compared to those in the low-risk group, indicating differential drug sensitivities. In summary, we established a robust DRGs signature comprising BTN3A1, CEBPA, KCNAB2, TBX21, and MYC, which showed strong prognostic value and predictive potential for immune status and drug sensitivity in OS. Notably, functional experiments confirmed that BTN3A1 acted as a tumor suppressor in OS, highlighting it as a promising therapeutic target.

PCM did not enhance cell viability when IGF1R was silenced or inhibited with linsitinib, demonstrating the pathway's essential role. Finally, PCM also conferred resistance to osimertinib in patient-derived EGFR-mutant lung adenocarcinoma cell lines. Our study demonstrates that the intra-tumoral bacteria C. indologenes may significantly influence sensitivity to osimertinib or impart resistance in EGFR-mutant lung adenocarcinoma by activating the IGF1R signaling pathway.

Here, we applied our recently developed single-cell lineage tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations...In addition, in an FLT3-ITD-positive AML patient-derived xenograft (PDX) mouse model, the CC-90009 and quizartinib combination showed significantly higher anti-tumor efficacy and prolonged overall survival compared to either treatment alone...Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil pre-existing transcriptional features of treatment vulnerability in hematological cancers and elucidate strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-mutated AML.

Through drug sensitivity analysis, several drugs exhibited significant correlation with risk score, and molecular docking illustrated that both dactolisib and linsitinib were capable of binding tightly with most signature genes, making them potential candidates for targeted therapeutic approaches of LGG. Thus, this model can stratify LGG patients with distinct gene expression features, immune landscape, genomic instability and microbiota features. By stratifying patients with risk score, this risk model may improve the accuracy of prognostic prediction for LGG patients, which might provide new insights into the molecular targeted therapy for individual treatment in a risk score-specific manner.

Four drugs (PAC.1, OSI.906, WH.4.023, BMS.536924) were identified as chemotherapeutic drugs in Glioma. Finally, the expression of prognostic genes in tumor was significantly higher than that in normal tissue. New prognostic genes CD79B, STXBP4, DDHD1, FKBP1B, and TRAM2 were identified for glioma through the new perspective of lysine acetylation, suggesting their importance in the development of the disease and offering potential insights for diagnosis and treatment.

Fucoidan treatment decreased proliferation in neuroblastoma cells by interfering with the signal transduction of HGF, IGF2, and VEGF, which substantially increased cellular susceptibility to specific growth factor receptor inhibitors.

In vivo, oral Linsitinib attenuated fibrosis and inflammation in bleomycin-induced pulmonary fibrosis, inhibiting IGF-1R phosphorylation. Ex vivo, human IPF lung explants confirmed Linsitinib mitigated fibrosis and collagen accumulation via the IGF-1/IGF-1R/PPARγ axis. These findings suggest that Linsitinib exerts its effects against fibrosis by targeting IGF-1R-driven signaling pathways, making it a potential therapeutic agent for IPF.

Loss of BCOR function is associated with more aggressive retinoblastoma cell line growth and chemoresistance, at least in part due to increased IGF1R signaling. Inhibiting IGF1R pharmacologically had a marked anti-tumor effect in aggressive retinoblastoma lacking BCOR, suggesting it as a new therapeutic target, although this still needs to be confirmed in clinical samples with BCOR mutations.