Insulin-like Growth Factor-1 Receptor Inhibitor Research Articles

Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy.

Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves’ disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves’ disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO.

Insulin-Like Growth Factor 1 Receptor Drives Hepatocellular Carcinoma Growth and Invasion by Activating Stat3-Midkine-Stat3 Loop.

Activation of the insulin-like growth factor 1 receptor (IGF-1R)-mediated Janus kinase (JAK)1/2-Stat3 pathway contributes to hepatocarcinogenesis. Specifically, a previous study showed that IGF-1R inhibition downregulated Midkine expression in hepatocellular carcinoma (HCC). The present study investigated the role of IGF-1R-JAK1/2-Stat3 and Midkine signaling in HCC, in addition to the molecular link between the IGF-1R-Stat3 pathway and Midkine. The expression levels of IGF-1R, Stat3, and Midkine were measured using reverse transcription-quantitative PCR, following which the association of IGF-1R with Stat3 and Midkine expression was evaluated in HCC. The molecular link between the IGF-1R-Stat3 pathway and Midkine was then investigated in vitro before the effect of IGF-1R-Stat3 and Midkine signaling on HCC growth and invasion was studied in vitroand in vivo. IGF-1R, Stat3, and Midkine mRNA overexpressions were all found in HCC, where the levels of Stat3 and Midkine mRNA correlated positively with those of IGF-1R. In addition, Midkine mRNA level also correlated positively with Stat3 mRNA expression in HCC tissues. IGF-1R promoted Stat3 activation, which in turn led to the upregulation of Midkine expression in Huh7 cells. Similarly, Midkine also promoted Stat3 activation through potentiating JAK1/2 phosphorylation. Persistent activation of this Stat3-Midkine-Stat3 positive feedback signal loop promoted HCC growth and invasion, the inhibition of which resulted in significant antitumor activities both in vitroand in vivo. Constitutive activation of the IGF-1R-mediated Stat3-Midkine-Stat3 positive feedback loop is present in HCC, the inhibition of which can serve as a potential therapeutic intervention strategy for HCC.

Impaired brain fractalkine-CX3CR1 signaling is implicated in cognitive dysfunction in diet-induced obese mice

IntroductionA diet high in saturated fat is well known to affect neuronal function and contribute to cognitive decline in experimental animals and humans. Fractalkine released from neurons acts on its...

A phase-1 trial of linsitinib (OSI-906) in combination with bortezomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

We report results of a phase-1 study evaluating the safety and anti-cancer activity of the small molecule insulin-like growth factor-1 receptor (IGF-1R) inhibitor, linsitinib combined with bortezomib, and dexamethasone in relapsed/refractory multiple myeloma. Nineteen patients were enrolled across four dose-escalation cohorts (75–150 mg bid). The maximum tolerated dose of linsitinib was 125 mg. The most frequent Grade 3/4 AEs occurring in ≥10% of patients were thrombocytopenia (53%), bone pain (26%), neutropenia (21%), diarrhea (14%), anemia (14%), rash (10%), and lung infection (10%). Study discontinuation due to treatment-related AEs was low (16%). Across all cohorts the ORR was 61% (95% CI: 28.9–75.6%). Three partial response or greater and one stable disease were observed in proteasome inhibitor (PI) refractory patients (n = 5). Median PFS was 7.1 months (95% CI: 3.6–NA). Linsitinib plus bortezomib and dexamethasone demonstrate a manageable safety profile while the clinical benefit particularly in PI refractory patients warrants further exploration.

Inceptor counteracts insulin signalling in β-cells to control glycaemia.

Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure1-3. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene Iir). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R4, and a mannose6-phosphate receptordomain that is also found in the IGF2 receptor (IGF2R)5. Knockout mice that lack inceptor (Iir-/-) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from Iir-/- mice showed an increase in the activation of INSR-IGF1R in Iir-/- pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific Iir-/- knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR-IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR-IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR-IGF1R in β-cells. Together, our findings show that inceptor shields insulin-producing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR-IGF1R sensitization and diabetes therapy.

Thyroid hormone mediates cardioprotection against postinfarction remodeling and dysfunction through the IGF-1/PI3K/AKT signaling pathway

AimsSevere cardiovascular diseases, such as myocardial infarction or heart failure, can alter thyroid hormone (TH) secretion and peripheral conversion, leading to low triiodothyronine (T3) syndrome. Accumulating evidence suggests that TH has protective properties against cardiovascular diseases and that treatment with TH can effectively reduce myocardial damage after myocardial infarction (MI). Our aim is to investigate the effect of T3 pretreatment on cardiac function and pathological changes in mice subjected to MI and the underlying mechanisms. Main methodsAdult male C57BL/6 mice underwent surgical ligation of the left anterior descending coronary artery (LAD) (or sham operation) to establish MI model. T3, BMS-754807 (inhibitor of insulin-like growth factor-1 receptor (IGF-1R)) or vehicle was administered before surgery. Key findingsCompared with the MI group, the T3 pretreatment group exhibited significant attenuation of the myocardial infarct area, inhibition of cardiomyocyte apoptosis and fibrosis, and improved left ventricular function after MI. In addition, T3 exhibited an enhanced potency to stimulate angiogenesis and exert anti-inflammatory effects by reducing the levels of serum inflammatory cytokines after MI. However, all of these protective effects were inhibited by the IGF-1R inhibitor BMS-754807. Moreover, the protein expression of IGF-1/PI3K/AKT signaling-related proteins, such as IGF-1, IGF-1R, phosphorylated PI3K (p-PI3K) and p-AKT was significantly upregulated in MI mice that received T3 pretreatment, and BMS-754807 pretreatment blocked the upregulation of the expression of these signaling-related proteins. SignificanceT3 pretreatment can protect the heart against dysfunction post-MI, which may be mediated by the activation of the IGF-1/PI3K/AKT signaling pathway.

Inhibition of SNCG suppresses the proliferation of lung cancer cells induced by high glucose.

Lung cancer is the most common cancer type worldwide and the leading cause of cancer-related mortality. Diabetes is closely associated with the occurrence, development and prognosis of lung cancer. Therefore, the present study aimed to investigate whether SNCG could affect the proliferation of lung cancer cells induced by high glucose. Lung cancer cells induced by high glucose simulated the pathologies of patients with lung cancer with diabetes in vitro. The proliferation of HBE cells and lung cancer cells after transfection and treatment of glucose was detected using Cell Counting Kit-8 assay. The mRNA expression levels of synuclein γ (SNCG), insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) in HBE cells and lung cancer cells alone, or cells induced by high glucose were analyzed via reverse transcription-quantitative (RT-q)PCR analysis. Moreover RT-qPCR analysis was used to determine the transfection efficiencies. The clone formation ability, migration and inflammation of lung cancer cells after high glucose induction and transfection were detected using clone formation, wound healing and ELISA assays. The protein expression levels of SNCG, IGF-1, IGF-1R, ERK 1/2, phosphorylated (p)-ERK1/2 and JNK in lung cancer cells after high glucose induction and transfection were determined using western blot analysis. The results suggested that high glucose significantly promoted the proliferation of A549, NCI-H1975 and SK-MES-1 cells at 24 and 48 h, as well as upregulated the expression levels of SNCG, IGF-1 and IGF-1R. Knockdown of SNCG suppressed the proliferation, clone formation ability and migration, but alleviated inflammation in A549 cells induced by high glucose. Knockdown of SNCG suppressed the expression levels of SNCG, IGF-1, IGF-1R, ERK1/2 and p-ERK1/2, while it promoted JNK expression in A549 cells induced by high glucose. The effect of AXL1717 (an IGF-1R inhibitor) treatment on cells was consistent with that of SNCG knockdown. In conclusion, inhibition of SNCG suppresses proliferation of lung cancer cells induced by high glucose.

Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer.

Although radiation therapy for advanced colorectal cancer (CRC) is very effective in some patients, treatment resistance limits its efficacy. Insulin-like growth factor 1 receptor (IGF1R) can affect tumor responsiveness and sensitivity to radiation in several cancer types. Herein, we studied the underlying function of IGF1R in the resistance of advanced CRC to radiation therapy and the possible use of drugs targeting IGF1R to overcome this resistance in patients with CRC. Differences in the expression levels of the IGF1R were assessed in CRC samples from patients who were radiosensitive or radioresistant. Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for in vitro studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807. We assessed radiosensitivity in these human CRC cells lines by examining their proliferation and colony formation, as well as cell cycle analysis. Activation of the Akt pathway was assessed using western blotting. Compared with tissues from radiosensitive patients, higher IGF1R expression levels were found in patients with radiation-resistant colorectal cancer, while BMS-754807 had improved radiosensitivity and reversed radiation tolerance in both colorectal cancer cell lines. Pre-treatment with BMS-754807 prior to irradiation inhibited Akt phosphorylation, induced cell cycle arrest, and increased DNA damage. Therefore, the IGF1R contributes to radiation resistance of CRC cells in vitro. This study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.

Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway.

Skeletal muscle atrophy is an important feature of cancer cachexia, which can be induced by chemotherapy, and affects the survival and quality of life of cancer patients seriously. No specific drugs for cancer cachexia have been applied in clinical practice. This study explored the therapeutic effect of linalool (LIN) on cisplatin (DDP) induced skeletal muscle atrophy. In vivo, LIN can improve skeletal muscle weight loss, anorexia, muscle strength decline and other cachexia symptoms caused by cisplatin treatment in a Lewis lung cancer tumor bearing mouse model, and cause no adverse effects on the anti-tumour effect. LIN treatment decreased the expression of muscle RING-finger protein-1 (MuRF1) and Atrogin1(MAFbx) in muscle, and the activation of insulin-like growth factor-1 (IGF-1)/protein kinase B (Akt)/forkhead box O (FoxO) pathway was observed. In vitro, LIN alleviated DDP induced C2C12 myotube atrophy, and IGF-1 receptor inhibitor Picropodophyllin (PIC), which had no adverse effect on C2C12 myotube cells, could reverse the protective effect of LIN. These results indicate that LIN down-regulates the expression of Atrogin1 and MuRF1 through the IGF-1/Akt/FoxO pathway, alleviating DDP-induced muscle atrophy and improving cachexia symptoms. LIN has the potential to be developed as a drug against cancer cachexia.

Unraveling the Resistance of IGF-Pathway Inhibition in Ewing Sarcoma.

Simple SummaryThe insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and survival. After promising results with targeting and inhibiting the receptor in vitro, multiple different IGF1R targeting compounds have been clinically tried but showed limited efficacy. Here we discuss several possible resistance mechanisms which could explain why IGF1R targeting fails in the clinic and discuss possible ways to overcome these resistances.Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor.

STEM-16. IGF1/N-CADHERIN/b-CATENIN/CLUSTERIN SIGNALING AXIS MEDIATES ADAPTIVE RADIORESISTANCE IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is composed of heterogeneous tumor cell populations including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by increased cell-cell adhesion, slower proliferation, an elevation of stemness properties and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of b-catenin at the cell surface, which suppressed Wnt/ b-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. Restoration of wild type N-cadherin, but not mutant N-cad lacking b-catenin binding region, led to induce radioresistance in N-cadherin knockout GSCs, indicating the importance of the binding between N-cadherin and b-catenin. We also demonstrated that N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin (PPP), a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation. Moreover, the elevation of N-cad and Clusterin are related to prognosis of GBM in the TCGA dataset. In conclusion, our data indicate that IGF1R inhibitor can block the N-cadherin-mediated resistance pathway. Our study deepens our understanding of adaptive radioresistance during repeated irradiation in GBM, and validates the IGF1/N-cadherin/b-catenin/Clusterin signaling axis as a novel target for radio-sensitization, which has direct therapeutic applicability.

Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor.

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.

IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas

The insulin-like growth factor 1 receptor (IGF-1R) governs several signaling pathways for cell proliferation, survival, and anti-apoptosis. Thus, targeting IGF-1R appears as a reasonable rationale for tumor treatment. However, clinical studies showed that inhibition of IGF-1R has very limited efficacy due to the development of resistance to IGF-1R blockade in tumor cells. Here, we discovered that prolonged treatment of colon cancer cells with IGF-1R inhibitors (BMS-754807 and GSK1838705A) stimulates p70 KDa ribosomal protein S6 kinase 1 (p70S6K1) activation, a well-known kinase signaling for cell survival. We also found that p70S6K1 activation by IGF-1R inhibition is independent of K-Ras and PIK3CA mutations that frequently occur in colon cancer. Besides the increased p70S6K1 phosphorylation, the phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) was elevated in the cells treated with BMS-754807. Interestingly, the increases in MEK1/2 and p70S6K1 phosphorylation were also observed when cells were subjected to the treatment of AKT inhibitor or genetic knockdown of AKT2 but not AKT1, suggesting that AKT2 inhibition stimulates MEK1/2 phosphorylation to activate p70S6K1. Conversely, inhibition of MEK1/2 by MEK1/2 inhibitor (U0126) or knockdown of MEK1 and MEK2 by corresponding mek1 and mek2 siRNA enhanced AKT phosphorylation, indicating mutual inhibition between AKT and MEK. Furthermore, the combination of BMS-754807 and U0126 efficiently decreased the cell viability and increased cleaved caspase 3 and apoptosis in vitro and in vivo. Our data suggest that the treatment of colon tumor cells with IGF-1R inhibitors stimulates p70S6K1 activity via MEK1/2 to promote survival, providing a new strategy for colorectal cancer therapeutics.

Abstract 5677: Recurrent transcriptionally active ESR1 fusions render therapeutic vulnerabilities to kinase inhibition in advanced breast cancer

Abstract Background: We recently reported two ESR1 fusions (ESR1-YAP1 and ESR1-PCDH11X) that drive endocrine therapy (ET) resistance and metastasis in estrogen receptor positive (ER+) metastatic breast cancer (MBC) (PMC6171747). Here we report additional ESR1 fusions with diverse C-terminal partner genes - ESR1-DAB2, ESR1-GYG1, ESR1-SOX9, ESR1-ARNT2, ESR1-PCMT1 and ESR1-ARID1B. Their functional characteristics and effects on kinase biology will be described. Methods: ESR1 fusions were identified by RNA-seq in MBC using ChimeraScan to detect fusion junction reads. ESR1 fusion cDNA constructs were expressed in ER+ breast cancer cell lines. An alamarBlue assay assessed cell proliferation. RNA-seq followed by mRNA-qPCR assessed the transcriptional properties. A scratch wound assay assessed cell motility. A Kinase Inhibitor Pulldown (KIP) mass spectrometry-based assay was conducted to examine ESR1 fusion-driven druggable kinases. Results: All fusions retained the first 6 exons (e6) of ESR1, fused in-frame to C-terminal sequences of diverse partner genes. In addition to ESR1-YAP1 and ESR1-PCDH11X fusions, ESR1-SOX9 and ESR1-ARNT2 drove fulvestrant-resistant growth. RNA-seq revealed fusion-specific transcriptional signatures indicating enrichment of estrogen responsive and epithelial-to-mesenchymal transition (EMT) pathways that were confirmed by mRNA-qPCR. Transcriptionally active ESR1 fusions also promoted hormone-independent cell motility. KIP profiling demonstrated an increase in protein abundance of multiple receptor tyrosine kinases including RET and insulin like growth factor 1 receptor (IGF1R) in T47D cells expressing active ESR1 fusion proteins, both of which have been previously implicated in driving ET and MBC. Both proteins were also elevated in a patient-derived xenograft naturally harboring the ESR1-YAP1 fusion. Combinatorial inhibition of RET and IGF1R significantly suppressed ESR1 fusion-driven cell growth in vitro. Neither transcriptional activation nor kinase upregulation was observed in other ESR1-e6 fusions. Lastly, we report recurrent examples of specific known active ESR1 fusions: ESR1-PCDH11X (3 examples) (TEMPUS unpublished data) and ESR1-ARNT2 (2 examples) (PMC6872491). Conclusion: A subset of ESR1-e6 fusions are active, drive ET resistance and metastasis/EMT in experimental models. When ESR1 is fused in-frame with another transcriptional regulator, activity is predictable. However, recurrent partners that have non-transcriptional roles (PCDH11X) suggests cDNA expression-based functional screens should be continued. A common pattern of kinase activation indicates that ESR1 fusion specific therapeutic strategies could be devised. Citation Format: Xuxu Gou, Jonathan Lei, Beom-Jun Kim, Meenakshi Anurag, Sinem Seker, Saif Rehman, Adrian V. Lee, Kevin White, Michael Caldwell, Jonathan Ball, Dan R. Robinson, Matthew J. Ellis. Recurrent transcriptionally active ESR1 fusions render therapeutic vulnerabilities to kinase inhibition in advanced breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5677.

Intermittent parathyroid hormone improves orthodontic retention via insulin-like growth factor-1.

This study aimed to investigate the effects of intermittent parathyroid hormone (iPTH) on the stability of orthodontic retention and to explore the possible regulatory role of insulin-like growth factor-1 (IGF-1) in this process. Forty-eight 6-week-old male Wistar rats were adopted in this study. An orthodontic relapsing model was established to investigate the effects of iPTH on orthodontic retention. In vitro, an immortalized mouse cementoblast cell line OCCM-30 was detected by flow cytometry to study the effects of iPTH on cell proliferation and apoptosis. By application of a specific IGF-1 receptor inhibitor, the role of IGF-1 was also explored. In vivo study found that daily injection of PTH significantly reduced the relapsing distance. Histological staining and ELISA assay showed faster periodontal regeneration during retention period in PTH group with increased RANKL/OPG ratio and greater amount of OCN, ALP, and IGF-1 in gingival cervical fluid (GCF). Cell experiment revealed that iPTH promoted proliferation and suppressed apoptosis of cementoblast. IGF-1 receptor inhibitor significantly restrained the anabolic effect of iPTH on OCCM-30 cells. These findings suggest that iPTH could improve the stability of tooth movement by promoting periodontal regeneration. IGF-1 is essential in mediating the anabolic effects of iPTH.

IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer's Disease Transgenic Mouse Model.

Aging is a major risk factor for Alzheimer’s disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice (df/df). Subsequently, a reduction in gliosis, amyloid-β (Aβ) plaque deposition, and Aβ1–40/42 concentrations were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease. To assess the role of IGF-1 in AD, 9–10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups including control vehicle (DMSO) and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. The brain penetrant inhibitor was given ip. at 1 mg/kg/day. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble Aβ1–40/42. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment.

Insulin-like growth factor 1 triggers salt secretion machinery in fish under acute salinity stress

Timely adjustment of osmoregulation upon acute salinity stress is essential for the survival of euryhaline fish. This rapid response is thought to be tightly controlled by hormones; however, there are still questions unanswered. In this work, we tested the hypothesis that the endocrine hormone, insulin-like growth factor 1 (Igf1), a slow-acting hormone, is involved in the activation of salt secretion mechanisms in euryhaline medaka (Oryzias melastigma) during acclimation to acute salinity stress. In response to a 30-ppt seawater (SW) challenge, Na+/Cl- secretion was enhanced within 0.5 h, with concomitant organization of ionocyte multicellular complexes and without changes in expression of major transporters. Igf1 receptor inhibitors significantly impair the Na+/Cl- secretion and ionocyte multicellular complex responses without affecting transporter expression. Thus, Igf1 may activate salt secretion as part of the teleost response to acute salinity stress by exerting effects on transporter function and enhancing the formation of ionocyte multicellular complexes. These findings provide new insights into hormonal control of body fluid ionic/osmotic homeostasis during vertebrate evolution.

Proteomic analysis of combined IGF1 receptor targeted therapy and chemotherapy identifies signatures associated with survival in breast cancer patients.

Clinical, epidemiological and experimental data identified the insulin-like growth factor-1 receptor (IGF1R) as a candidate therapeutic target in oncology. While this paradigm is based on well-established biological facts, including the potent anti-apoptotic and cell survival capabilities of the receptor, most Phase III clinical trials designed to target the IGF1R led to disappointing results. The present study was aimed at evaluating the hypothesis that combined treatment composed of selective IGF1R inhibitor along with classical chemotherapy might be more effective than individual monotherapies in breast cancer treatment. Analyses included comprehensive measurements of the synergism achieved by various combination regimens using the CompuSyn software. In addition, proteomic analyses were conducted to identify the proteins involved in the synergistic killing effect at a global level. Data presented here demonstrates that co-treatment of IGF1R inhibitor along with chemotherapeutic drugs markedly improves the therapeutic efficiency in breast cancer cells. Of clinical relevance, our analyses indicate that high IGF1R baseline expression may serve as a predictive biomarker for IGF1R targeted therapy. In addition, we identified a ten-genes signature with potential predictive value. In conclusion, the use of a series of bioinformatics tools shed light on some of the biological pathways that might be responsible for synergysm in cancer therapy.

Teprotumumab in Thyroid-Associated Ophthalmopathy: Rationale for Therapeutic Insulin-Like Growth Factor-I Receptor Inhibition.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune component of Graves' disease for which no currently available medical therapy provides reliable and safe benefit. Based on insights generated experimentally over the past several decades, the insulin-like growth factor-I receptor (IGF-IR) has been implicated in the pathogenesis of TAO. Furthermore, an IGF-IR inhibitor, teprotumumab, has emerged from 2 clinical trials as a promising treatment for active, moderate to severe TAO. This brief review intends to provide an overview of the rationale underlying the development of teprotumumab for this disease. It is possible that teprotumumab will soon take its place in our therapeutic armamentarium for active TAO.