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

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

Comprehensive analysis of telomere and aging-related signature for predicting prognosis and immunotherapy response in lung adenocarcinoma. (PubMed, J Cardiothorac Surg) - "The risk score exhibited robust prognostic capabilities, offering novel insights for assessing immunotherapy. This will provide a new direction to achieve personalized and precise treatment of LUAD in the future."

Biomarker • IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Linsitinib inhibits proliferation and induces apoptosis of both IGF-1R and TSH-R expressing cells. (PubMed, Front Immunol) - "Cells were treated with ten rising concentrations of either Linsitinib, Linsitinib + Metformin, Teprotumumab, or a blocking TSH-R mAb (K1-70). In addition, in the TSH-R-Ab blocking bioassay, Linsitinib and the tested compounds demonstrated strong inhibition across all ten dilutions (100%). Linsitinib effectively induces apoptosis and inhibits proliferation of both IGF-1R and TSH-R expressing target cells, therefore demonstrating its therapeutic potential to block the reported crosstalk of the two mediators in autoimmune TED."

Journal • Immunology • Ophthalmology • Thyroid Eye Disease • CASP3 • CASP7

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. (PubMed, PLoS One) - "In addition, our results showed that pretreatment with linsitinib inhibited IGF-1-induced phosphorylation of IGF-1Rβ at Tyr1135, Akt at Ser473, and ERK in the OFs of patients with TAO. These results indicate that linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion in the OFs of TAO patients by suppressing the PI3K/Akt and ERK pathways, validating the use of linsitinib as a novel therapeutic agent for TAO."

Journal • Endocrine Disorders • Grave’s Disease • Immunology • Oncology • Ophthalmology • Thyroid Eye Disease • IGF1

Linsitinib Decreases Thyrotropin-Induced Thyroid Hormone Synthesis by Inhibiting Crosstalk Between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors in Human Thyrocytes In Vitro and In Vivo in Mice. (PubMed, Thyroid) - " The IGF-1R antagonist Lins inhibited bTSH-stimulated hTG and hTPO protein expression in primary cultures of hThyros and fT4 levels in mice. We suggest that thyroid function studies be monitored when Lins is administered to humans, for example, if it is used to treat TED."

Journal • Preclinical • Ophthalmology • Thyroid Eye Disease • LINS1

Transcriptomic profiling of thyroid eye disease orbital fat demonstrates differences in adipogenicity and IGF-1R pathway. (PubMed, JCI Insight) - "Additionally, our data showed that linsitinib, a small-molecule inhibitor of IGF-1R, effectively reduced adipogenesis in TED orbital fibroblasts in vitro, suggesting its potential utility as a therapeutic agent. Our findings reveal that, beyond immune dysfunction, abnormal IGF-1R signaling leading to enhanced adipogenesis is a crucial pathogenic mechanism in TED."

Journal • Endocrine Disorders • Inflammation • Ophthalmology • Thyroid Eye Disease

Targeting the insulin-like growth factor-1 receptor to overcome imatinib resistance in chronic myeloid leukemia. (PubMed, Discov Oncol) - "Moreover, silencing of IGF-1R by small interfering ribonucleic acid increased the sensitivity of CML cell lines to imatinib, indicating that IGF-1R could be a strategic target for overcoming resistance. These findings highlight the therapeutic potential of linsitinib and that IGF-1R inhibition may improve the treatment outcomes of patients with imatinib-resistant CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP3 • CASP7

Therapeutic Potential of Growth Hormone in Peripheral Nerve Injury: Enhancing Schwann Cell Proliferation and Migration Through IGF-1R-AKT and ERK Signaling Pathways. (PubMed, Glia) - "Moreover, the GH-induced proliferation and migration of SCs were significantly diminished by the inhibition of the IGF-1R pathway, achieved through pre-treatment with Linsitinib. The outcomes of this investigation suggest that GH can significantly enhance the proliferation and migration of SCs, presenting it as a viable option for PNI repair."

Journal

Metformin Impairs Linsitinib Anti-Tumor Effect on Ovarian Cancer Cell Lines. (PubMed, Int J Mol Sci) - "Ovarian cancer (OC) remains one of the leading causes of cancer-related mortality among women. Statistical analyses were performed using ordinary one-way or two-way ANOVA, followed by Tukey's or Šídák's multiple comparison tests. While linsitinib shows promise as a therapeutic option for OC, further research is needed to identify agents that could synergize with it to enhance its therapeutic efficacy, like the combination with standard chemotherapy in OC (carboplatin and paclitaxel)."

Journal • Preclinical • Diabetes • Metabolic Disorders • Oncology • Ovarian Cancer • Solid Tumor • Type 2 Diabetes Mellitus • IGF1

Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy. (PubMed, J Clin Invest) - "Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti-programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy."

IO biomarker • Journal • Oncology • CAFs • CD8 • CXCL12 • IGF1 • IGF2

Catalytic activities of wild-type C. elegans DAF-2 kinase and dauer-associated mutants. (PubMed, FEBS J) - "Unlike the human insulin or IGF-1 receptor kinases, DAF-2 kinase was poorly inhibited by the small-molecule inhibitor linsitinib...These mutations caused a complete loss of kinase function in vitro. Our biochemical investigations provide new insights into DAF-2 kinase function, and the approach should be useful for studying other mutations to shed light on DAF-2 signaling in C. elegans physiology."

Journal • IGF1 • IR