linsitinib (ASP7487) / Astellas, Sling Therap - LARVOL DELTA

Development and validation of a novel disulfidptosis-related gene signature for prediction of survival and immune microenvironment in osteosarcoma by WGCNA analysis. (PubMed, Discov Oncol) - "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."

Gene Signature • IO biomarker • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BTLA • BTN3A1 • CEBPA • LAG3 • PD-L1 • PD-L2 • TBX21

Chryseobacterium indologenes mediates resistance to osimertinib by activating the IGF1R pathway in EGFR-mutant lung adenocarcinoma. (PubMed, bioRxiv) - "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."

Journal • Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • EGFR

Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia. (PubMed, Cancer Res) - "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..."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3 • GSPT1 • IR

Construction and validation of a disulfidptosis-related risk assessment model for prediction of prognosis, immune microenvironment, drug therapy and microbiota in patients with low grade glioma. (PubMed, Int J Surg) - "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."

Journal • Tumor mutational burden • Brain Cancer • Glioma • Oncology • Solid Tumor • CD4 • CD8 • TMB

Spatial Transcriptomics Identifies Insulin-Like Growth Factor 2 (IGF2) as a Mediator of Nephron Progenitor Cell Renewal (KIDNEY WEEK 2025) - "To validate the functional role of the top candidate, we cultured E13.5 mouse fetal kidney explants and treated them with recombinant IGF2, linsitinib (IGF1R inhibitor), or insulin...Spatial transcriptomics was indispensable for uncovering these in situ ligand receptor relationships, which are obscured in dissociated assays. Our findings identify a potential mechanism underlying the clinical observation that children born from pregnancies with uncontrolled maternal diabetes have small kidney size and increased proteinuria."

Diabetes • Gestational Diabetes • Metabolic Disorders • Renal Disease • IGF2 • JAG1

Lipid raft-mediated insulin signaling sustains AKT activation and contributes to osimertinib resistance in NSCLC cells (AACR-NCI-EORTC 2025) - "Moreover, linsitinib, an insulin receptor (InsR) inhibitor, effectively blocked AKT activation in AR cells, indicating that AKT activation was sustained by insulin signaling in AR cells. FLOT1 plays a pivotal role in assembling insulin signaling components within lipid rafts, enhancing aberrant AKT activation. Targeting FLOT1 re-sensitizes resistant cells to osimertinib, highlighting it as a potential molecular target to overcome EGFR-TKI resistance."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FLOT1 • IR

Fucoidan Treatment Leads to Attenuated Growth Factor Signaling and Reduced Proliferation in Neuroblastoma Cells. (PubMed, Anticancer Res) - "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."

Journal • Neuroblastoma • Oncology • Solid Tumor • IGF2

Role of lysine acetylation-related genes in the diagnosis and prognosis of glioma. (PubMed, Sci Rep) - "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."

Journal • Brain Cancer • CNS Tumor • Developmental Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor • CD79B

Epigallocatechin-3-Gallate Attenuates Benign Prostatic Hyperplasia Development via Regulating Firmicutes to Inhibit Gastric Secretion of Insulin-Like Growth Factor-1. (PubMed, Cell Biol Int) - "Mechanistically, IGF-1 stimulated prostate cell proliferation (RWPE-1/WPMY-1) and suppressed apoptosis via PI3K/AKT/mTOR activation, while the IGF-1 antagonist Linsitinib reversed these effects...Our findings position EGCG as a promising intervention for MetS-associated BPH, simultaneously targeting microbial dysbiosis and IGF-1 signaling. This study not only elucidates the Firmicutes-IGF-1 axis in BPH pathogenesis but also highlights the therapeutic potential of dietary polyphenols in metabolic urological disorders."

Journal • Benign Prostatic Hyperplasia • Metabolic Disorders • Transplantation • IGF1

Targeting insulin-like growth factor 1 signaling with Linsitinib to modulate fibroblast plasticity and attenuate pulmonary fibrosis. (PubMed, Int Immunopharmacol) - "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."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • COL1A1 • COL3A1 • IGF1 • PPARG • TGFB1

Oncolytic Herpes Simplex Virus and Radiation Therapy Synergize with IGF1R-Targeted Therapy to Enhance Glioblastoma Treatment (ASGCT 2025) - "The synergistic interaction of the triple combination therapy—including oHSV, RTx, and IGF1R blockade (e.g., OSI-906 or PPP)—was quantified using SynergyFinder analysis... Our study provides preclinical evidence for the efficacy of a triple combination therapy of oHSV, RTx, and IGF1R blockade, supporting its potential for future clinical evaluation in patients. Disease Focus of Abstract:Cancer Solid Tumors"

Brain Cancer • Breast Cancer • CNS Tumor • Glioblastoma • Herpes Simplex • Oncology • Solid Tumor • CASP3 • IGF2 • YAP1

Synergistic anti-cancer effects of dual IGF-1R and EGFR targeting in uveal melanoma (AACR 2025) - "Moreover, Linsitinib and gefitinib co-treatment dramatically increased cleaved PARP protein, an apoptotic maker. Our research suggests that dual targeting of IGF-1R and EGFR could be a novel treatment strategy to inhibit uveal melanoma metastatic dissemination and growth."

Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • EGFR

Genomic amplification of MCL1 as a therapeutic target for osteosarcoma (AACR 2025) - "The treatment for OS that combines surgery with chemotherapy, which consists of a four-drug combination of doxorubicin (DOX), cisplatin (CDDP), high-dose methotrexate (MTX), and ifosfamide, was established in 1970s, and it is still used as a standard therapy...Additionally, the combination of MIK665 with IGF-1R inhibitors, including OSI906, AEW541, and AZD3463, induced synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling in OS cells...Moreover, the combination therapy of AZD5991 with OSI906 also reduced tumor growth in the NOS-10 xenograft model. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, observed in nearly half of OS patients, may act as a predictive biomarker for combination therapy with an Mcl-1 inhibitor and an IGF1-R inhibitor."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IGF1 • NOS1 • PIP5K1A

IGF-1 signaling pathway activation promotes axonal regeneration and repair: a mechanism study on catalpol-induced functional recovery after ischemic stroke. (PubMed, J Ethnopharmacol) - "Our research elucidates that catalpol improves neurological recovery in ischemic stroke by regulating the IGF-1 signaling pathway to promote axonal regenerative repair, providing a new perspective for addressing the challenge of functional recovery in ischemic stroke."

Journal • Cardiovascular • Ischemic stroke • IGF1 • MBP • SPP1

Targeted immunotherapies for Graves' thyroidal & orbital diseases. (PubMed, Front Immunol) - "They include rituximab, an anti-CD20 monoclonal antibody which causes rapid B cell depletion; ATX-GD-59, an antigen specific immunotherapy which restores immune tolerance to thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 co-stimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor blocking monoclonal antibody...Both tocilizumab (anti-interleukin 6 receptor monoclonal antibody) and sirolimus (mammalian target of rapamycin inhibitor) showed promise in glucocorticoid resistant active disease. Teprotumumab, an anti-insulin-like growth factor-1 receptor monoclonal antibody, demonstrated remarkable all-round efficacy across a wide disease spectrum. Linsitinib, a dual small molecule inhibitor of insulin-like growth factor-1 receptor and insulin receptor, displayed significant proptosis reduction in its phase 2b/3 study. Finally, Batoclimab, an anti-neonatal fragment crystallizable receptor monoclonal antibody,..."

Journal • Review • Endocrine Disorders • Grave’s Disease • Immunology • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain • Thyroid Eye Disease • CD40LG • IL6R • IR

Treatment landscape in SDH-deficient gastrointestinal stromal tumors: A systematic review and meta-analysis (Sarcoma-RC 2025) - "Treatments examined included Imatinib, Sunitinib, Regorafenib, Pazopanib, Masitinib, Vandetanib, Guadecitabine, and Linsitinib. Legal entity responsible for the study The authors. Funding Has not received any funding."

Retrospective data • Review • Stroma • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

BCOR loss promotes both retinoblastoma growth and susceptibility to IGF1R inhibition. (PubMed, Neuro Oncol) - "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."

Journal • Eye Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • BCL6 • BCOR • IGF1

Bioinformatics-based identification of mirdametinib as a potential therapeutic target for idiopathic pulmonary fibrosis associated with endoplasmic reticulum stress. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "The molecular docking energies of mirdametinib with protein targets ranged from - 5.1643 to - 8.0154 kcal/mol, while those of linsitinib ranged from - 5.6031 to - 7.902 kcal/mol. Molecular docking and animal experiments were performed to validate the therapeutic potential of identified compounds, with mirdametinib showing specific effects in a murine bleomycin-induced pulmonary fibrosis model. In vitro experiments indicated that mirdametinib may alleviate pulmonary fibrosis by reducing ERS via the PI3K/Akt/mTOR pathway. Our findings highlight 11 ERSRGs as predictors of IPF and demonstrate the feasibility of bioinformatics in drug discovery for IPF treatment."

Journal • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Characterization of linsinitinib nanocrystals as a potential therapy for thyroid eye disease (ARVO 2025) - "These investigational products are dosed systemically and likely to have similar side effect profiles as teprotumumab...Linsitinib SR retains the ability to inhibit IGF-1R phosphorylation. Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Ophthalmology • IGF1

Linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion by suppressing PI3K/Akt and ERK pathway in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (ARVO 2025) - "Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Clinical • Ocular Inflammation • Ophthalmology • IGF1

Exploring common genomic biomarkers to disclose common drugs for the treatment of colorectal cancer and hepatocellular carcinoma with type-2 diabetes through transcriptomics analysis. (PubMed, PLoS One) - "Finally, cGBs-guided seven candidate drugs (Digitoxin, Camptosar, AMG-900, Imatinib, Irinotecan, Midostaurin, and Linsitinib) as the common treatment against T2D, CRC and HCC were identified through molecular docking, cross-validation, and ADME/T (Absorption-Distribution-Metabolism-Excretion-Toxicity) analysis. Most of these findings received support by the literature review of diseases specific individual studies. Thus, this study offers valuable insights for researchers and clinicians to improve the diagnosis and treatment of CRC and/or HCC patients during the co-occurrence of T2D."

Biomarker • Journal • Colorectal Cancer • Diabetes • Hepatocellular Cancer • Hepatology • Metabolic Disorders • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • CXCL1 • FOXC1 • GATA2 • IL6 • MIR195 • MIR34A • MMP9 • SPP1

Targeting insulin-like growth factor 1 receptor restricts development and severity of secondary lymphedema in mice. (PubMed, iScience) - "Linsitinib restricted enlargement of small lymphatics and tissue swelling during lymphedema development, likely by inhibiting IGF1R-driven vascular endothelial growth factor-C (VEGF-C) synthesis by macrophages. Importantly, linsitinib profoundly reduced tissue swelling in mice with chronic lymphedema suggesting IGF signaling as a therapeutic target for this disease."

Journal • Preclinical • Inflammation • IGF1 • IGFBP5 • VEGFC

Screening of common genomic biomarkers to explore common drugs for the treatment of pancreatic and kidney cancers with type-2 diabetes through bioinformatics analysis. (PubMed, Sci Rep) - "Finally, we identified six top-ranked drug molecules (NVP.BHG712, Irinotecan, Olaparib, Imatinib, RG-4733, and Linsitinib) as potential common treatments for PC, KC and T2D during their co-existence, supported by the literature reviews. Thus, this bioinformatics study provides valuable insights and resources for developing a genome-guided common treatment strategy for PC and/or KC patients who are also suffering from T2D."

Biomarker • Journal • Diabetes • Genito-urinary Cancer • Hepatology • Kidney Cancer • Metabolic Disorders • Oncology • Pancreatic Cancer • Solid Tumor • Type 2 Diabetes Mellitus • BIRC5 • E2F7 • MUC1 • RRM2 • TOP2A

Extension Study of Two Doses of Linsitinib in Subjects With Active, Moderate to Severe Thyroid Eye Disease (TED) (clinicaltrials.gov) - P2/3 | N=75 | Recruiting | Sponsor: Sling Therapeutics, Inc. | Phase classification: P2b ➔ P2/3

Phase classification • Endocrine Disorders • Ophthalmology • Thyroid Eye Disease

Sling Therapeutics Announces Positive Topline Results from Phase 2b/3 LIDS Clinical Trial of Oral Small Molecule Linsitinib in Patients with Thyroid Eye Disease (PRNewswire) - P2b/3 | N=90 | LIDS (NCT05276063) | Sponsor: Sling Therapeutics, Inc. | "Sling Therapeutics, Inc...announced topline efficacy and safety data from the Phase 2b/3 LIDS trial of linsitinib in patients with active, moderate to severe TED....No drug-related hearing impairment reported (1 unrelated report out of 29 patients); 0% tinnitus placebo-adjusted rate; 3% rate of hyperglycemia (1 report out of 29 patients with no intervention required); 0% menstrual cycle changes reported; Treatment emergent AEs greater than or equal to 10%: diarrhea (20.7%), headache (20.7%), nausea (20.7%), fatigue (17.2%), ALT increase (17.2%), hyperhidrosis (13.8%), AST increase (10.3%), and muscle spasms (10.3%)...The Company is engaging with regulatory authorities to discuss the confirmatory Phase 3 trial design, which is on track to commence in 2025. Full results of this Phase 2b/3 trial will be presented at an upcoming medical conference."

New P3 trial • P2/3 data • Thyroid Eye Disease