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Frontiers in Endocrinology 2023Graves' disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid...
INTRODUCTION
Graves' disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland. Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD. Therapeutic options to treat TED are very limited and novel treatments need to be developed. In the present study we investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR) on the disease outcome of GD and TED.
METHODS
Linsitinib was administered orally for four weeks with therapy initiating in either the early ("active") or the late ("chronic") phases of the disease. In the thyroid and the orbit, autoimmune hyperthyroidism and orbitopathy were analyzed serologically (total anti-TSHR binding antibodies, stimulating anti TSHR antibodies, total T4 levels), immunohistochemically (H&E-, CD3-, TNFa- and Sirius red staining) and with immunofluorescence (F4/80 staining). An MRI was performed to quantify tissue remodeling inside the orbit.
RESULTS
Linsitinib prevented autoimmune hyperthyroidism in the state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining. In the state of the disease linsitinib had its main effect in the orbit. Linsitinib reduced immune infiltration of T-cells (CD3 staining) and macrophages (F4/80 and TNFa staining) in the orbita in experimental GD suggesting an additional, direct effect of linsitinib on the autoimmune response. In addition, treatment with linsitinib normalized the amount of brown adipose tissue in both the and group. An MRI of the group was performed and revealed a marked decrease of inflammation, visualized by F MR imaging, significant reduction of existing muscle edema and formation of brown adipose tissue.
CONCLUSION
Here, we demonstrate that linsitinib effectively prevents development and progression of thyroid eye disease in an experimental murine model for Graves' disease. Linsitinib improved the total disease outcome, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves' Disease. Our data support the use of linsitinib as a novel treatment for thyroid eye disease.
Topics: Animals; Mice; Graves Disease; Graves Ophthalmopathy; Hyperthyroidism; Imidazoles; Protein Kinase Inhibitors; Receptor, IGF Type 1
PubMed: 37435490
DOI: 10.3389/fendo.2023.1211473 -
Saudi Journal of Biological Sciences Feb 2022Colorectal cancer is one of the most common cancers. Regorafenib is used in patients with metastatic colorectal cancer and sometimes, the cancer cells become resistant...
Colorectal cancer is one of the most common cancers. Regorafenib is used in patients with metastatic colorectal cancer and sometimes, the cancer cells become resistant to the drug. However, increased IGF-1R activity is associated with the invasion of cancer cells. Therefore, it is thought that inhibiting IGF-1R by Linsitinib and Aspirin, the resistance of colorectal cancer cells to Regorafenib can be reduced. SW48 colon cancer cell line was cultured, resistance to the regorafenib and exposed to Linsitinib and Aspirin. The treatment cytotoxicity, Flow cytometry for determine cancer stem cell markers, and the mRNA expression of CD133, CD44, CD24, IGF1-R, CDX2 and PTEN were done. Then C57BL/6J mice tumor model was produced and treated with regorafenib, aspirin, and linsitinib. At least, Clinical symptoms, the levels of IL-6, and IL-1β, TNF-α and MCP-1 in the colon tissues and sera were assessed. The linsitinib and aspirin as the IGF1-R antagonists inhibited colon cancer resistance against regorafenib, stem-cell like colon cancer cells growth, decreased expression of CD133, CD44, CD24, and also increased CDX2, PTEN gene expression. In the canceroous mice, linsitinib, aspirin and regorafenib treatment enhanced Body weight and survival, and also decreased fecal blood, number of tumors in colon and Inflammatory cytokines levels in serum and colon tissues. In this study, we obtained the best in-vitro and in-vivo result of colon cancer treatment when combinitation therapy Linsitinib, Aspirin, and Regorafenib was used, and could prevent tumor resistance, stem cell producing, pathological interaction and disease activity index.
PubMed: 35197754
DOI: 10.1016/j.sjbs.2021.10.019 -
Autophagy Aug 2021Induction of macroautophagy (hereafter termed autophagy) is a strategy to improve the outcome of antineoplastic therapies by facilitating the induction of immunogenic... (Review)
Review
Induction of macroautophagy (hereafter termed autophagy) is a strategy to improve the outcome of antineoplastic therapies by facilitating the induction of immunogenic cancer cell death and the consequent immune recognition of malignant cells. We analyzed 65,000 distinct compounds by means of a phenotypic discovery platform for autophagy induction and identified the IGF1R (insulin like growth factor 1 receptor) inhibitor picropodophyllin (PPP) as a potent inducer of autophagic flux. We found that PPP acts on-target, as an inhibitor of the tyrosine kinase activity of IGF1R and enhances the release of adenosine triphosphate, ATP, from stressed and dying cancer cells in vitro, thereby improving the therapeutic efficacy of chemoimmunotherapy in cancer-bearing mice. This PPP effect was phenocopied by another IGF1R inhibitor, linsitinib. Moreover, in human triple-negative breast cancer, phosphorylation of IGF1R correlates with reduced autophagy, an unfavorable local immune profile and poor prognosis. In summary, IGF1R inhibition may constitute a novel strategy for the treatment of cancer in the context of chemoimmunotherapy.
Topics: Animals; Autophagy; Cell Proliferation; Humans; Imidazoles; Podophyllotoxin; Protein Kinase Inhibitors; Pyrazines; Receptor, IGF Type 1
PubMed: 34110249
DOI: 10.1080/15548627.2021.1936934 -
Cancer Chemotherapy and Pharmacology Apr 2016This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an...
PURPOSE
This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single (14)C-linsitinib dose.
METHODS
Five patients received a single oral dose of 150 mg (14)C-linsitinib, followed by collection of blood, plasma, urine, and feces for 10 days. The collected material was analyzed for total radioactivity, linsitinib, and metabolites. The safety of 150 mg of unlabeled linsitinib administered twice daily until disease progression was also assessed.
RESULTS
The median time to reach the maximum plasma concentration of linsitinib was 3.0 h, median maximum plasma concentration was 1789 ng/mL, median terminal half-life was 2.4 h, and median apparent oral clearance was 12.45 L/h. After a single dose of (14)C-linsitinib, 5.44 and 76.4 % of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen linsitinib metabolites (M1-M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of (14)C-linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled linsitinib.
CONCLUSIONS
(14)C-linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination.
Topics: Aged; Female; Humans; Imidazoles; Male; Metabolic Networks and Pathways; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Pyrazines
PubMed: 26972330
DOI: 10.1007/s00280-016-2999-5 -
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 -
ACS Infectious Diseases Oct 2022ATP provides energy in the biosynthesis of cellular metabolites as well as regulates protein functions through phosphorylation. Many ATP-dependent enzymes are...
ATP provides energy in the biosynthesis of cellular metabolites as well as regulates protein functions through phosphorylation. Many ATP-dependent enzymes are antibacterial and anticancer targets including human kinases acted on by most of the successful drugs. In search of new chemotherapeutics for tuberculosis (TB), we screened repurposing compounds against the essential glutamine synthase (GlnA1) of (Mtb) and identified linsitinib, a clinical-stage drug originally targeting kinase IGF1R/IR as a potent GlnA1 inhibitor. Linsitinib has direct antimycobacterial activity. Biochemical, molecular modeling, and target engagement analyses revealed the inhibition is ATP-competitive and specific in Mtb. Linsitinib also improves autophagy flux in both Mtb-infected and uninfected THP1 macrophages, as demonstrated by the decreased p-mTOR and p62 and the increased lipid-bound LC3B-II and autophagosome forming puncta. Linsitinib-mediated autophagy reduces intracellular growth of wild-type and isoniazid-resistant Mtb alone or in combination with bedaquiline. We have demonstrated that an IGF-IR/IR inhibitor can potentially be used to treat TB. Our study reinforces the concept of targeting ATP-dependent enzymes for novel anti-TB therapy.
Topics: Adenosine Triphosphate; Anti-Bacterial Agents; Glutamine; Humans; Imidazoles; Isoniazid; Lipids; Mycobacterium tuberculosis; Protein Kinase Inhibitors; Pyrazines; Receptor, IGF Type 1; TOR Serine-Threonine Kinases; Tuberculosis
PubMed: 36048501
DOI: 10.1021/acsinfecdis.2c00278 -
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 -
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 -
Science (New York, N.Y.) May 2016Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress...
Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Drug Resistance, Neoplasm; Glioblastoma; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Insulin-Like Growth Factor I; Macrophages; Mice; Mice, Inbred Strains; NFATC Transcription Factors; Neoplasm Recurrence, Local; Neoplasms, Experimental; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Picolinic Acids; Pyrazines; Receptor, IGF Type 1; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; STAT6 Transcription Factor; Signal Transduction; Tumor Microenvironment
PubMed: 27199435
DOI: 10.1126/science.aad3018 -
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