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Frontiers in Endocrinology 2023Graves' disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces...
INTRODUCTION
Graves' disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED) as the most common extra thyroidal manifestation of Graves' disease. In TED, the TSHR cross talks with the insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts leading to inflammation, deposition of hyaluronan and adipogenesis. The bone marrow may play an important role in autoimmune diseases, but its role in Graves' disease and TED is unknown. Here, we investigated whether induction of experimental Graves' disease and accompanying TED involves bone marrow activation and whether interference with IGF-1R signaling prevents this activation.
RESULTS
Immunization of mice with TSHR resulted in an increase the numbers of CD4-positive T-lymphocytes (p ≤0.0001), which was normalized by linsitinib (p = 0.0029), an increase of CD19-positive B-lymphocytes (p= 0.0018), which was unaffected by linsitinib and a decrease of GR1-positive cells (p= 0.0038), which was prevented by linsitinib (p= 0.0027). In addition, we observed an increase of Sca-1 positive hematopietic stem cells (p= 0.0007) and of stromal cell-derived factor 1 (SDF-1) (p ≤0.0001) after immunization with TSHR which was prevented by linsitinib (Sca-1: p= 0.0008, SDF-1: p ≤0.0001). TSHR-immunization also resulted in upregulation of CCL-5, IL-6 and osteopontin (all p ≤0.0001) and a concomitant decrease of the immune-inhibitory cytokines IL-10 (p= 0.0064) and PGE2 (p ≤0.0001) in the bone marrow (all p≤ 0.0001). Treatment with the IGF-1R antagonist linsitinib blocked these events (all p ≤0.0001). We further demonstrate a down-regulation of arginase-1 expression (p= 0.0005) in the bone marrow in TSHR immunized mice, with a concomitant increase of local arginine (p ≤0.0001). Linsitinib induces an upregulation of arginase-1 resulting in low arginase levels in the bone marrow. Reconstitution of arginine in bone marrow cells prevented immune-inhibition by linsitinib.
CONCLUSION
Collectively, these data indicate that the bone marrow is activated in experimental Graves' disease and TED, which is prevented by linsitinib. Linsitinib-mediated immune-inhibition is mediated, at least in part, by arginase-1 up-regulation, consumption of arginine and thereby immune inhibition.
Topics: Mice; Animals; Graves Ophthalmopathy; Arginase; Bone Marrow; Graves Disease; Receptors, Thyrotropin; Autoimmune Diseases; Arginine
PubMed: 37810891
DOI: 10.3389/fendo.2023.1252727 -
Cancer Medicine Jun 2017The aim of this study is to evaluate the efficacy of insulin-like growth factor 1 receptor (IGF-1R) inhibitor Linsitinib, in esophageal squamous cell carcinoma (ESCC),...
The aim of this study is to evaluate the efficacy of insulin-like growth factor 1 receptor (IGF-1R) inhibitor Linsitinib, in esophageal squamous cell carcinoma (ESCC), and to characterize special biomarker to screen Linsitinib-sensitive patients as well as explore the molecular-resistant mechanism to Linsitinib in ESCC. Our study evaluated the sensitivity of insulin-like growth factor 1 receptor (IGF-1R) inhibitor, Linsitinib in ESCC cells with MTT assay. After Linsitinib treatment, the expressions of downstream signaling molecules and apoptosis pathways were measured by western blot. And the antitumor effect of Linsitinib and JSH-23, an inhibitor of nuclear factor-κB transcriptional activity, was analyzed both as single agent and in combination in ESCC. Apoptosis, cell viability, and clonogenic survival analysis were also investigated. The sensitivity of Linsitinib was relatively variable in patient-derived primary ESCC cells as well as in human commercial cell lines. And the downstream AKT/mTOR and ERK signaling pathways were inhibited by Linsitinib, while phosphorylation level of NF-κB p65 was obviously activated to reduce apoptosis effect in Linsitinib-resistant cell lines. Most importantly, blockage of NF-κB activity by JSH-23 could sensitize resistant cells to Linsitinib treatment. Results from this study demonstrated that the intrinsic resistance to Linsitinib was predominantly mediated by NF-κB activation in ESCC. Moreover, combination of Linsitinib and JSH-23 as therapy provides a novel strategy to overcome resistance to Linsitinib in ESCC.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Interleukin-6; Interleukin-8; NF-kappa B; Phenylenediamines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyrazines; RNA, Messenger; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured
PubMed: 28440057
DOI: 10.1002/cam4.1068 -
Theranostics 2022Accumulating studies manifest that BTB and CNC homology 1 (BACH1) facilitates multiple malignancies progression and metastasis, and targeting the BACH1 pathway enhances...
Accumulating studies manifest that BTB and CNC homology 1 (BACH1) facilitates multiple malignancies progression and metastasis, and targeting the BACH1 pathway enhances antitumor efficacy. Nevertheless, the exact mechanism of BACH1 promoting growth and metastasis and its therapeutic significance in hepatocellular carcinoma (HCC) remain unclear. The expression of BACH1 in human HCC specimens and HCC cell lines was analyzed by quantitative RT-PCR (RT-qPCR), western blot, and immunohistochemistry (IHC). The invasiveness and metastasis of HCC cells and were evaluated using transwell assays and orthotopic xenograft models. The luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to explore the transcriptional regulation of insulin-like growth factor 1 receptor () and protein tyrosine kinase 2 () by BACH1. BACH1 was prominently upregulated in human HCC samples and elevated BACH1 expression was associated with poor overall survival (OS) and high recurrence rates of HCC patients. BACH1 facilitated growth and metastasis of HCC by upregulating cell motility-related genes and . Notably, insulin-like growth factor 2 (IGF2), the ligand of IGF1R, in turn upregulated BACH1 expression through the IGF1R-ERK1/2-ETS1 cascades, thus forming a positive feedback loop to provoke HCC growth and metastasis. Moreover, combining IGF1R inhibitor linsitinib with PTK2 inhibitor defactinib prominently suppressed BACH1-mediated HCC growth and metastasis. These results demonstrated the tumorigenic and pro-metastatic role of BACH1 in HCC, which could be a promising biomarker for predicting poor prognosis and selecting patients who could benefit from combination therapy of IGF1R-targeted and PTK2-directed.
Topics: Basic-Leucine Zipper Transcription Factors; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Focal Adhesion Kinase 1; Humans; Insulin-Like Growth Factor II; Liver Neoplasms; Neoplasm Metastasis; Receptor, IGF Type 1
PubMed: 35154476
DOI: 10.7150/thno.65775 -
Clinical Cancer Research : An Official... Apr 2020Most gastrointestinal stromal tumors (GIST) have activating mutations of , or uncommonly . Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT),...
PURPOSE
Most gastrointestinal stromal tumors (GIST) have activating mutations of , or uncommonly . Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor, in patients with WT GIST.
PATIENTS AND METHODS
A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (FDG) metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results.
RESULTS
Twenty patients were accrued in a 6-month period. Grade 3-4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively.
CONCLUSIONS
Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.
Topics: Adolescent; Adult; Electron Transport Complex II; Female; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imidazoles; Male; Middle Aged; Mutation; Patient Safety; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrazines; Receptor, IGF Type 1; Treatment Outcome; Young Adult
PubMed: 31792037
DOI: 10.1158/1078-0432.CCR-19-1069 -
The Oncologist Oct 2016Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials.Linsitinib, a... (Comparative Study)
Comparative Study Randomized Controlled Trial
LESSONS LEARNED
Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials.Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC.Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients.
BACKGROUND
Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC.
METHODS
In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m intravenously or 2.3 mg/m orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0-2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression.
RESULTS
Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5-3.6) and 1.2 (95% CI, 1.1-1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2-7.6) and 3.4 (95% CI, 1.8-5.6) months for topotecan and linsitinib, respectively (p = .71). Grade 3/4 adverse events (>5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for linsitinib.
CONCLUSION
Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Pyrazines; Receptor, IGF Type 1; Small Cell Lung Carcinoma; Topotecan
PubMed: 27694157
DOI: 10.1634/theoncologist.2016-0220 -
The Lancet. Oncology Apr 2015Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma.
METHODS
In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989.
FINDINGS
Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related.
INTERPRETATION
Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma.
FUNDING
Astellas.
Topics: Adrenocortical Carcinoma; Adult; Aged; Aged, 80 and over; Disease-Free Survival; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Placebos; Protein Kinase Inhibitors; Pyrazines
PubMed: 25795408
DOI: 10.1016/S1470-2045(15)70081-1 -
Mediators of Inflammation 2019Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some...
Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some subsets of patients. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is tightly regulated and plays critical roles in mediating cell proliferation, growth, and survival. Thus, IGF-1R may be a potential therapeutic target for patients with different malignancies. However, its mechanism in NPC is not fully investigated. Linsitinib is an oral small molecule and is a tyrosine kinase inhibitor (TKI) of IGF-1R, which has been known for antitumor effects used widely. Here, we evaluated the proliferation and radiosensitivity of NPC cell lines (CNE-2 and SUNE-1) after linsitinib treatment. We found that linsitinib suppresses IGF-1-induced cell proliferation through inhibiting Akt and ERK phosphorylation. Moreover, linsitinib further boosted IR-induced DNA damage, G2-M cell cycle delay, and apoptosis in NPC cells. Finally, linsitinib reversed radioresistant NPC cells by decreasing the phosphorylation of IGF-1R. Our data indicated that the combination of linsitinib and IR and targeting IGF-1R by linsitinib could be a promising therapeutic strategy for NPC.
Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; DNA Damage; Humans; Imidazoles; Nasopharyngeal Carcinoma; Phosphorylation; Protein Kinase Inhibitors; Pyrazines; Radiation, Ionizing; Receptor, IGF Type 1
PubMed: 31467485
DOI: 10.1155/2019/5497467 -
The International Journal of... Jun 2014In this study we investigated the effect of linsitinib on the reversal of multidrug resistance (MDR) mediated by the overexpression of the ATP-binding cassette (ABC)...
In this study we investigated the effect of linsitinib on the reversal of multidrug resistance (MDR) mediated by the overexpression of the ATP-binding cassette (ABC) subfamily members ABCB1, ABCG2, ABCC1 and ABCC10. Our results indicate for the first time that linsitinib significantly potentiate the effect of anti-neoplastic drugs mitoxantrone (MX) and SN-38 in ABCG2-overexpressing cells; paclitaxel, docetaxel and vinblastine in ABCC10-overexpressing cells. Linsitinib moderately enhanced the cytotoxicity of vincristine in cell lines overexpressing ABCB1, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, linsitinib significantly increased the intracellular accumulation and decreased the efflux of [(3)H]-MX in ABCG2-overexpressing cells and [(3)H]-paclitaxel in ABCC10-overexpressing cells. However, linsitinib, at a concentration that reversed MDR, did not significantly alter the expression levels of either the ABCG2 or ABCC10 transporter proteins. Furthermore, linsitinib did not significantly alter the intracellular localization of ABCG2 or ABCC10. Moreover, linsitinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner. Overall, our study suggests that linsitinib attenuates ABCG2- and ABCC10-mediated MDR by directly inhibiting their function as opposed to altering ABCG2 or ABCC10 protein expression.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Interactions; Drug Resistance, Multiple; HEK293 Cells; Humans; Imidazoles; Lung Neoplasms; Mitoxantrone; Models, Molecular; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Paclitaxel; Protein Kinase Inhibitors; Pyrazines
PubMed: 24726739
DOI: 10.1016/j.biocel.2014.03.026 -
Neuro-oncology Jul 2022Diffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although...
BACKGROUND
Diffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.
METHODS
Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.
RESULTS
GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.
CONCLUSION
Our study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.
Topics: Brain Stem Neoplasms; Child; Glioma; Humans; Immunotherapy, Adoptive; Receptor, IGF Type 1; Receptor, Insulin; T-Lymphocytes
PubMed: 34964902
DOI: 10.1093/neuonc/noab300 -
PloS One 2023Androgen deprivation therapy (ADT) is the standard of care for high risk and advanced prostate cancer; however, disease progression from androgen-dependent prostate...
Androgen deprivation therapy (ADT) is the standard of care for high risk and advanced prostate cancer; however, disease progression from androgen-dependent prostate cancer (ADPC) to lethal and incurable castration-resistant prostate cancer (CRPC) and (in a substantial minority of cases) neuroendocrine prostate cancer (NEPC) is common. Identifying effective targeted therapies is challenging because of acquired resistance to established treatments and the vast heterogeneity of advanced prostate cancer (PC). To streamline the identification of potentially active prostate cancer therapeutics, we have developed an adaptable semi-automated protocol which optimizes cell growth and leverages automation to enhance robustness, reproducibility, and throughput while integrating live-cell imaging and endpoint viability assays to assess drug efficacy in vitro. In this study, culture conditions for 72-hr drug screens in 96-well plates were established for a large, representative panel of human prostate cell lines including: BPH-1 and RWPE-1 (non-tumorigenic), LNCaP and VCaP (ADPC), C4-2B and 22Rv1 (CRPC), DU 145 and PC3 (androgen receptor-null CRPC), and NCI-H660 (NEPC). The cell growth and 72-hr confluence for each cell line was optimized for real-time imaging and endpoint viability assays prior to screening for novel or repurposed drugs as proof of protocol validity. We demonstrated effectiveness and reliability of this pipeline through validation of the established finding that the first-in-class BET and CBP/p300 dual inhibitor EP-31670 is an effective compound in reducing ADPC and CRPC cell growth. In addition, we found that insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib is a potential pharmacological agent against highly lethal and drug-resistant NEPC NCI-H660 cells. This protocol can be employed across other cancer types and represents an adaptable strategy to optimize assay-specific cell growth conditions and simultaneously assess drug efficacy across multiple cell lines.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Androgens; Reproducibility of Results; Androgen Antagonists; Cell Survival; Cell Line, Tumor; Receptors, Androgen; Automation
PubMed: 37815978
DOI: 10.1371/journal.pone.0287126