NVP-AEW541 / Novartis - LARVOL DELTA

Advances in the role of the IGF signaling system in myelodysplastic syndromes and acute myeloid leukemia. (PubMed, Front Oncol) - "The potential therapeutic implications of targeting the IGF signaling pathway, including the role of NVP-AEW541 and NVP-ADW742 effectively suppressing AML cell proliferation and enhancing chemotherapy sensitivity, are also explored. By integrating current findings, this review provides novel insights into the mechanistic role of IGF signaling in MDS and AML and its therapeutic implications, thereby guiding future research and potential clinical applications. Given the challenges, such as pathway redundancy and therapy resistance, further investigations are necessary to validate IGF-targeted therapies and optimize their clinical utility in hematologic malignancies."

Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • IGF1 • IGF2

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

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

Dual Targeting Of PD-1 And IGF1R: Enhancing Anti-Tumor Responses In Epithelial Ovarian Cancer (ESGO 2025) - "Methodology C57BL/6 mice with established peritoneal ovarian cancer were injected with single or combined anti-PD-1 and AEW-541 treatment, and their survival was evaluated...IGF1R inhibitor combined with anti-PD-1 may result in enhanced anti-tumor activity. Thus, restoring the anti-tumor immune response by IGF1R targeting in combination with immunotherapy may be an effective therapy for EOC."

Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • PD-1

IGF1R inhibition and PD-1 blockade improve anti-tumor immune response in epithelial ovarian cancer. (PubMed, Front Oncol) - "Additionally, anti-PD-1/IGF1R treatment increased DC by 34% compared with AEW-541 and 40% with anti-PD-1...RNA-seq data analysis indicated that anti-PD-1/IGF1R led to a more potent immune response, as reflected by altered gene expression levels related to anti-tumor immune response, compared with either treatment alone. These findings provide novel evidence that IGF1R axis inhibition combined with PD-1 blockade may be an effective therapeutic strategy for selected EOC patient populations."

IO biomarker • Journal • Oncology • Ovarian Cancer • Solid Tumor • CD8 • IGF1

Signaling effect, combinations, and clinical applications of triciribine. (PubMed, J Chemother) - "Triciribine (TCN) is a tricyclic nucleoside. Although a single dose of TCN demonstrated limited activity in solid tumors at the clinical level, combinations of TCN with various agents, such as specific inhibitors, tyrosine kinase inhibitor dasatinib, ErbB inhibitor tipifarnib, IGF1-R inhibitor NVP-AEW541, mTORC1 inhibitor RAD-001, TNF-related apoptosis-inducing ligand, PPARγ agonist, 1,25(OH)2D3, gemcitabine, and paclitaxel, have been reported to be efficient against various malignancies such as pancreatic, breast, prostate cancer, insulinoma, gut neuroendocrine tumor, and hepatocellular carcinoma at the preclinical level. Other than malignancies, through Akt inhibition activity, TCN has also been demonstrated potential for treating lung injuries, including those encountered in COVID-19 infections."

Journal • Review • Breast Cancer • Endocrine Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Hepatology • Infectious Disease • Neuroendocrine Tumor • Novel Coronavirus Disease • Oncology • Pancreatic Cancer • Prostate Cancer • Respiratory Diseases • Solid Tumor • IGF1

Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability. (PubMed, Front Cell Neurosci) - "These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin...In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures."

Journal • Preclinical • Pain • IGF1 • TRPV1

IGF-1R mediates crosstalk between nasopharyngeal carcinoma cells and osteoclasts and promotes tumor bone metastasis. (PubMed, J Exp Clin Cancer Res) - "The intricate interplay among IGF-1R, IGF-1, and GM-CSF highlights potential therapeutic targets for precise control of NPC bone metastasis, providing valuable insights for developing targeted interventions."

Journal • Hematological Malignancies • Musculoskeletal Diseases • Nasopharyngeal Carcinoma • Oncology • Pain • Solid Tumor • CSF2

COMBINATION OF IGF1R INHIBITION WITH PD-1 BLOCKADE RESULTS IN SIGNIFICANT ANTI-TUMORAL ACTIVITY IN EPITHELIAL OVARIAN CANCER (IGCS 2023) - "IGF1R inhibitor treatment significantly induced DC differentiation in AEW-541 pre-treated-DCs compared to control after 24 h. In addition, Differentiated AEW-541-treated-DCs significantly decreased EOC cell proliferation. In vivo experiment showed that combined anti-PD-1/IGF1R treatment decreased tumor weight compared to single treatments. Moreover, the anti-PD-1/IGF1R treatment significantly increased the conventional DCs compared to AEW-541 and anti-PD-1 treatments."

Oncology • Ovarian Cancer • Solid Tumor

COMBINATION OF IGF1R INHIBITION WITH PD-1 BLOCKADE RESULTS IN SIGNIFICANT ANTI-TUMORAL ACTIVITY IN EPITHELIAL OVARIAN CANCER (ESGO 2023) - "Methodology EOC cell lines were co-cultured with IGF1R inhibitor (AEW-541)-treated-DCs...IGF1R inhibitor combined with anti-PD-1 may result in enhanced anti-tumor activity. Thus, restoring the anti-tumor immune response by IGF1R targeting in combination with immunotherapy may be an effective therapy for EOC."

Oncology • Ovarian Cancer • Solid Tumor

Targeting the IGF1R signaling pathway inhibits cell growth and dissemination in BCOR mutant retinoblastoma (AACR 2023) - "Pharmacological inhibition of IGF1/IGF1R signaling using Lincitinib or AEW541 inhibited proliferation and migration in BCOR knockout retinoblastoma cells in vitro, and Lincitinib dramatically slowed xenograft growth in vivo, suggesting that induction of IGF1 represents an important downstream effector following BCOR loss. Our studies support a functional role for BCOR mutations in aggressive retinoblastoma, and suggest that this is mediated at least in part by increased IGF1R signaling, which represents a new therapeutic target for these malignant childhood tumors of the eye."

Eye Cancer • Oncology • Retinoblastoma • Solid Tumor • BCL6 • BCOR • IGF1

Sperm-carried IGF2 downregulated the expression of mitogens produced by Sertoli cells: A paracrine mechanism for regulating spermatogenesis? (PubMed, Front Endocrinol (Lausanne)) - "Subsequently, the experiments were repeated by pre-incubating SCs with the non-competitive insulin-like growth factor 1 receptor (IGF1R) inhibitor NVP-AEW541...In conclusion, sperm IGF2 seems to downregulate the expression of mitogens, which are known to be physiologically released by the SCs to promote gonocyte proliferation and spermatogonial fate adoption. These findings suggest the presence of paracrine regulatory mechanisms acting on the seminiferous epithelium during spermatogenesis, by which germ cells can influence the amount of mitogens released by the SCs, their sensitivity to FSH, and their rate of proliferation."

Journal • FGF2 • IGF2

COMBINATION OF IGF1R INHIBITION WITH PD-1 BLOCKADE RESULTS IN SIGNIFICANT ANTITUMORAL ACTIVITY IN EPITHELIAL OVARIAN CANCER (IGCS 2022) - " EOC cell lines were co-cultured with IGF1R inhibitor (AEW-541)-treated-DCs... IGF1R pathway inhibition in differentiated DCs suppressed EOC cell proliferation. IGF1R inhibitor combined with anti-PD-1 may result in enhanced anti-tumor activity. Thus, restoring the antitumor immune response by IGF1R targeting in combination with immunotherapy may be an effective therapy for EOC."

Oncology • Ovarian Cancer • Solid Tumor • CD8 • IGF1

The IGF-1R Inhibitor NVP-AEW541 Causes Insulin-Independent and Reversible Cardiac Contractile Dysfunction. (PubMed, Biomedicines) - "The systemic administration of NVP-AEW541 caused dose- and time-dependent impairment of glucose tolerance, growth, and cardiac function. Because cardiac insulin signaling was maintained in vivo but absent in vitro and because contractile function was not affected in vitro, a direct link between insulin resistance and contractile dysfunction appears unlikely."

Journal • CNS Disorders • Depression • Diabetes • Oncology • Psychiatry • IR

Sperm-carried IGF2 Downregulates Mitogens Released by Sertoli Cells: A Paracrine Mechanism of Spermatogenetic Regulation? (ENDO 2022) - "In the presence of NVP-AEW541, all these effects were counteracted, thus suggesting that they are mediated by the IGF1R. In conclusion, these results suggest the presence of a paracrine regulatory mechanism between germ cells and SCs by which the former can influence the proliferation of SCs, their sensitivity to FSH, and their function by reducing the secretion of germ cell mitogens."

Infertility • Sexual Disorders • FGF2 • IGF2

Mechanical Stress-Induced IGF-1 Facilitates col-I and col-III Synthesis via the IGF-1R/AKT/mTORC1 Signaling Pathway. (PubMed, Stem Cells Int) - "Moreover, the activation of pIGF-1R, pAKT, and pS6 was reduced by the IGF-1 neutralizing antibody and NVP-AEW541, and the activation of pS6 was reduced by rapamycin. In summary, these results suggested that mechanical stress promotes LFCs to produce IGF-1, which facilitates col-I and col-III synthesis via the IGF-1R/AKT/mTORC1 signaling pathway."

Journal • IGF1

Aerobic exercise and resistance exercise alleviate skeletal muscle atrophy through IGF-1/IGF-1R-PI3K/Akt pathway in mice with myocardial infarction. (PubMed, Am J Physiol Cell Physiol) - "AE and RE, safely and effectively, alleviate skeletal muscle atrophy by regulating the levels of myogenesis, protein degradation and cells apoptosis in mice with MI via activating IGF-1/IGF-1R-PI3K/Akt pathway."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Muscular Atrophy • Myocardial Infarction • Targeted Protein Degradation • IGF1

Abnormal Insulin-like Growth Factor 1 Signaling Regulates Neuropathic Pain by Mediating the Mechanistic Target of Rapamycin-Related Autophagy and Neuroinflammation in Mice. (PubMed, ACS Chem Neurosci) - "To corroborate the role of IGF1, we injected intrathecally IGF1R inhibitor (nvp-aew541) or anti-IGF1 neutralizing antibodies...IGF1R antagonism or IGF1 neutralization attenuated pain behaviors induced by CCI, relieved mTOR-related suppression of autophagy, and mitigated neuroinflammation in the spinal cord. These findings reveal that the abnormal IGF1/IGF1R signaling contributes to neuropathic pain by exacerbating autophagy dysfunction and neuroinflammation."

Journal • Preclinical • Immunology • Inflammation • Neuralgia • Pain • Peripheral Neuropathic Pain • IGF1 • mTOR

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer. (PubMed, Cancers (Basel)) - "Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNC cell lines...Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNC UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • IGF1 • IGF2 • PIK3CA

Maresin-1 induces cardiomyocyte hypertrophy through IGF-1 paracrine pathway. (PubMed, Am J Physiol Cell Physiol) - "Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K) / Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORα/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair."

Journal • Immunology • Inflammation • Multiple Sclerosis • IGF1

Targeting resistance mechanisms to CDK4/6 inhibitors in Ewing sarcoma with an IGF1R inhibitor drug combination strategy (AACR 2018) - "...Given the heightened efficacy of CDK4/6 inhibitors (CDK4/6i) in combination with other targeted drugs in breast cancer, as well as the known propensity of resistance to emerge with single agent targeted cancer therapy, we aimed to identify CDK4/6i resistance mechanisms and biologically relevant drug combinations in Ewing.To identify candidate resistance mechanisms, we performed a genome-wide lentiviral open-reading frame (ORF) rescue screen in two Ewing cell lines sensitive to the CDK4/6 inhibitors palbociclib and ribociclib and looked for genes that confer resistance to these drugs...We thus tested ribociclib and the IGF1R tool compound AEW541 in a panel of six Ewing cell lines in vitro...RPPA revealed enhanced suppression of the PI3K/mTOR pathway in the combination, a central cancer cell signaling axis. Taken together, these results suggest that IGF1R activation is an escape mechanism to CDK4/6i in Ewing and that dual targeting of CDK4/6 and IG

IO biomarker • Hormone Receptor Breast Cancer • Sarcoma

Targeting resistance mechanisms to CDK4/6 inhibitors in Ewing sarcoma with an IGF1R inhibitor drug combination strategy (AACR 2018) - "...Given the heightened efficacy of CDK4/6 inhibitors (CDK4/6i) in combination with other targeted drugs in breast cancer, as well as the known propensity of resistance to emerge with single agent targeted cancer therapy, we aimed to identify CDK4/6i resistance mechanisms and biologically relevant drug combinations in Ewing.To identify candidate resistance mechanisms, we performed a genome-wide lentiviral open-reading frame (ORF) rescue screen in two Ewing cell lines sensitive to the CDK4/6 inhibitors palbociclib and ribociclib and looked for genes that confer resistance to these drugs...We thus tested ribociclib and the IGF1R tool compound AEW541 in a panel of six Ewing cell lines in vitro...RPPA revealed enhanced suppression of the PI3K/mTOR pathway in the combination, a central cancer cell signaling axis. Taken together, these results suggest that IGF1R activation is an escape mechanism to CDK4/6i in Ewing and that dual targeting of CDK4/6 and IG

IO biomarker • Hormone Receptor Breast Cancer • Sarcoma

[VIRTUAL] Maresin 1 Induces Cardiomyocyte Hypertrophy Through RORα/IGF-1/PI3K/Akt Pathway (AHA 2020) - "Importantly, treatment with wortmannin or NVP-AEW541, inhibitors for PI3K or IGF-1 receptor, respectively, suppressed MaR1-induced cardiomyocyte hypertrophy, indicating that IGF-1/PI3K/Akt pathway is essential for MaR1-induced hypertrophy. In conclusion, MaR1 is a novel lipid mediator that induces physiological cardiomyocyte hypertrophy by activating RORα/IGF-1/PI3K/Akt pathway. Thus, MaR1 could coordinate the resolving process and tissue recovery in myocardial inflammation."

Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • Inflammation • IGF1

Effects of adipokine administration to the hypothalamic preoptic area on body temperature in rats. (PubMed, J Pharmacol Sci) - "The IGF-1-induced effect was inhibited by pretreatment with IGF binding protein 3 (IGFBP3) or NVP-AEW541 (NVP, a selective inhibitor of type 1 IGF receptor tyrosine kinase, IGF1R TK)...In addition, IGF-1 increased the IL-1β concentration in the microdialysate of POA perfusion, but did not increase the IL-1β concentration in the plasma or the PGE concentration in the microdialysate. These findings suggested that IGF-1 produced hyperthermia, which was mediated, at least a part, through an increased IL-1β concentration after activation of IGF1R TK in the POA, and the IGF-IGFBP system possibly participates in BT homeostasis in the POA."

Journal • Preclinical

Up-regulation of IGF-1R by mutant RAS in leukemia and potentiation of RAS signaling inhibitors by small molecule inhibition of IGF-1R (Clin Cancer Res) - “In vivo, NSG mice tail vein-injected with OCI-AML3-luc+ cells showed significantly lower tumor burden following one week of daily oral administration of 50 mg/kg NVP-AEW541 (IGF-1R inhibitor) combined with 25 mg/kg AZD6244 (MEK inhibitor), as compared to mice treated with either agent alone. Drug combination effects observed in cell-based assays were generalized to additional mutant RAS-positive neoplasms.” 

Preclinical • Oncology