RÉSUMÉ
Introduction: Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. Methods: A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responses from the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. Results: At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, n = 56), mean GO-QoL improvement was 15.22 (SE 2.82, n = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. Conclusion: The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.
Sujet(s)
Anticorps monoclonaux humanisés , Ophtalmopathie basedowienne , Humains , Ophtalmopathie basedowienne/traitement médicamenteux , Mâle , Femelle , Anticorps monoclonaux humanisés/usage thérapeutique , Adulte d'âge moyen , Résultat thérapeutique , Études de suivi , Adulte , Sujet âgé , Exophtalmie/traitement médicamenteux , Diplopie/traitement médicamenteux , Récepteur IGF de type 1/antagonistes et inhibiteursRÉSUMÉ
BACKGROUND: Thyroid eye disease (TED) can result in proptosis and ocular misalignment, leading to eye pain, diplopia, and vision loss. Teprotumumab, a humanized antibody against insulin-like growth factor 1 receptor, was approved in 2020 for the treatment of TED. The purpose of this study was to describe the effect of a full course of teprotumumab on ocular misalignment. METHODS: The medical records of patients who underwent treatment with teprotumumab for active moderate-to-severe TED at a single institution from April 2020 to September 2023 were reviewed retroactively. Sensorimotor examination was performed at each visit using simultaneous prism-cover testing. Demographic information and previous history of radioactive iodine, steroids, strabismus surgery, and smoking were extracted from the record for analysis. RESULTS: A total of 19 patients were treated during the study period, of whom 11 had strabismus and diplopia. The initial absolute horizontal misalignment in these 11 was 6.0Δ ± 1.5Δ, vertical misalignment was 7.7Δ ± 2.4Δ, and total misalignment was 11.5Δ ± 2.0Δ. On completion of treatment, these measurements decreased by 2.0Δ ± 1.5Δ, 2.2Δ ± 1.0Δ, and 3.2Δ ± 1.6Δ, respectively (P = 0.10, 0.02, and 0.04, resp.). Eight patients (73%) had a decrease in their strabismus, and 5 (46%) reported complete resolution of their diplopia at the final visit. No factors were predictive of which patients would have resolution of their misalignment. Of the remaining 3 patients who had no improvement in ocular alignment, 2 (66%) underwent strabismus surgery. Of the 8 patients with improvement of strabismus, only a single patient (13%) underwent strabismus surgery for persistent diplopia. CONCLUSIONS: In our study cohort, a full course of teprotumumab coincided with complete resolution of diplopia in 46% of patients and a decrease in strabismus in 73% of patients.
Sujet(s)
Anticorps monoclonaux humanisés , Diplopie , Ophtalmopathie basedowienne , Humains , Ophtalmopathie basedowienne/traitement médicamenteux , Mâle , Femelle , Anticorps monoclonaux humanisés/usage thérapeutique , Anticorps monoclonaux humanisés/administration et posologie , Adulte d'âge moyen , Études rétrospectives , Diplopie/physiopathologie , Sujet âgé , Adulte , Strabisme/chirurgie , Strabisme/traitement médicamenteux , Strabisme/physiopathologie , Perfusions veineuses , Récepteur IGF de type 1/antagonistes et inhibiteursRÉSUMÉ
The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound 27 exhibited potent cytotoxicity against HepG2 cells (IC50 = 0.62 ± 0.34 µM), significantly exceeding Sorafenib (IC50 = 1.62 ± 0.27 µM). Mechanistic investigations revealed that compound 27 potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound 27 potently inhibited (76.84% at 10 µM). Molecular modeling substantiated compound 27's strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound 27. These findings provide a promising drug candidate for the treatment of HCC patients.
Sujet(s)
Antinéoplasiques , Apoptose , Prolifération cellulaire , Inhibiteurs de protéines kinases , Récepteur IGF de type 1 , Thiazoles , Humains , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteur IGF de type 1/métabolisme , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cellules HepG2 , Thiazoles/composition chimique , Thiazoles/pharmacologie , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/synthèse chimique , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Apoptose/effets des médicaments et des substances chimiques , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/anatomopathologie , Tumeurs du foie/métabolisme , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/anatomopathologie , Carcinome hépatocellulaire/métabolisme , Mouvement cellulaire/effets des médicaments et des substances chimiques , Relation structure-activité , Simulation de docking moléculaire , Récepteurs des somatomédines/antagonistes et inhibiteurs , Récepteurs des somatomédines/métabolisme , Structure moléculaire , Lignée cellulaire tumorale , Sorafénib/pharmacologie , Sorafénib/composition chimique , Modèles moléculairesRÉSUMÉ
The allosteric inhibition of insulin-like growth factor receptor 1 kinase (IGF1RK) is a potential strategy to overcome selectivity barriers for targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives that have been reported as allosteric inhibitors of IGF1RK. We further studied the dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation: forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen-bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the positioning of chemical substituents with different pharmacophore features at the R1 indole ring influences molecular interactions and binding conformations of indole-butyl-amine derivatives and, hence, dramatically affects their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK.
Sujet(s)
Modèles moléculaires , Inhibiteurs de protéines kinases , Récepteur IGF de type 1 , Humains , Régulation allostérique , Site allostérique , Liaison hydrogène , Indoles/composition chimique , Indoles/pharmacologie , Simulation de dynamique moléculaire , Liaison aux protéines , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteur IGF de type 1/composition chimique , Récepteur IGF de type 1/métabolisme , Relation structure-activitéRÉSUMÉ
An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell- or fibroblast-specific knockout of Igf1r, the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl2-induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.
Sujet(s)
Anévrysme de l'aorte abdominale , Modèles animaux de maladie humaine , Facteur de croissance IGF-I , Récepteur IGF de type 1 , Animaux , Récepteur IGF de type 1/métabolisme , Récepteur IGF de type 1/antagonistes et inhibiteurs , Humains , Anévrysme de l'aorte abdominale/anatomopathologie , Anévrysme de l'aorte abdominale/traitement médicamenteux , Anévrysme de l'aorte abdominale/métabolisme , Anévrysme de l'aorte abdominale/prévention et contrôle , Facteur de croissance IGF-I/métabolisme , Mâle , Suidae , Souris , Transduction du signal/effets des médicaments et des substances chimiques , Souris de lignée C57BL , RatsRÉSUMÉ
Understanding kinase-inhibitor selectivity continues to be a major objective in kinase drug discovery. We probe the molecular basis of selectivity of an allosteric inhibitor (MSC1609119A-1) of the insulin-like growth factor-I receptor kinase (IGF1RK), which has been shown to be ineffective for the homologous insulin receptor kinase (IRK). Specifically, we investigated the structural and energetic basis of the allosteric binding of this inhibitor to each kinase by combining molecular modeling, molecular dynamics (MD) simulations, and thermodynamic calculations. We predict the inhibitor conformation in the binding pocket of IRK and highlight that the charged residues in the histidine-arginine-aspartic acid (HRD) and aspartic acid-phenylalanine-glycine (DFG) motifs and the nonpolar residues in the binding pocket govern inhibitor interactions in the allosteric pocket of each kinase. We suggest that the conformational changes in the IGF1RK residues M1054 and M1079, movement of the âºC-helix, and the conformational stabilization of the DFG motif favor the selectivity of the inhibitor toward IGF1RK. Our thermodynamic calculations reveal that the observed selectivity can be rationalized through differences observed in the electrostatic interaction energy of the inhibitor in each inhibitor/kinase complex and the hydrogen bonding interactions of the inhibitor with the residue V1063 in IGF1RK that are not attained with the corresponding residue V1060 in IRK. Overall, our study provides a rationale for the molecular basis of recognition of this allosteric inhibitor by IGF1RK and IRK, which is potentially useful in developing novel inhibitors with improved affinity and selectivity.
Sujet(s)
Simulation de dynamique moléculaire , Liaison aux protéines , Inhibiteurs de protéines kinases , Récepteur IGF de type 1 , Thermodynamique , Humains , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/métabolisme , Régulation allostérique , Récepteur IGF de type 1/composition chimique , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteur IGF de type 1/métabolisme , Site allostérique , Sites de fixation , Récepteur à l'insuline/composition chimique , Récepteur à l'insuline/métabolisme , Récepteur à l'insuline/antagonistes et inhibiteurs , Liaison hydrogèneRÉSUMÉ
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 in vivo tissue remodeling inside the orbit. Results: Linsitinib prevented autoimmune hyperthyroidism in the early state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining. In the late 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 early and late group. An in vivo MRI of the late group was performed and revealed a marked decrease of inflammation, visualized by 19F 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.
Sujet(s)
Maladie de Basedow , Ophtalmopathie basedowienne , Inhibiteurs de protéines kinases , Récepteur IGF de type 1 , Animaux , Souris , Maladie de Basedow/traitement médicamenteux , Ophtalmopathie basedowienne/traitement médicamenteux , Hyperthyroïdie , Imidazoles , Inhibiteurs de protéines kinases/usage thérapeutique , Récepteur IGF de type 1/antagonistes et inhibiteursRÉSUMÉ
Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin-like growth factor 1 receptor (IGF-1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF-1R to the nucleus. When the activation and/or nuclear translocation of IGF-1R was inhibited, Eri induced DNA damage and enhanced G2 /M arrest. In a xenograft model using the Eri-resistant SW480 cell line, the combination of Eri and the IGF-1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF-1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.
Sujet(s)
Tumeurs colorectales , Récepteur IGF de type 1 , Humains , Lignée cellulaire tumorale , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/génétique , Tumeurs colorectales/métabolisme , Altération de l'ADN , Facteur de croissance IGF-I , Inhibiteurs de protéines kinases/pharmacologie , Récepteur IGF de type 1/antagonistes et inhibiteurs , AnimauxRÉSUMÉ
High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.
Sujet(s)
Insulinorésistance , Récepteur IGF de type 1 , Tissu adipeux/métabolisme , Tissu adipeux blanc/métabolisme , Animaux , Anticorps monoclonaux humanisés , Alimentation riche en graisse/effets indésirables , Insuline/métabolisme , Facteur de croissance IGF-I/métabolisme , Lipides , Foie/métabolisme , Souris , Souris de lignée C57BL , Obésité/étiologie , Obésité/métabolisme , Récepteur IGF de type 1/antagonistes et inhibiteursRÉSUMÉ
The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting both IGF1R and pathways that antagonize autophagy, such as ERK-MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC. SIGNIFICANCE: Compensatory upregulation of IGF1R and ERK-MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.
Sujet(s)
Autophagie/physiologie , Carcinome du canal pancréatique/métabolisme , Extracellular Signal-Regulated MAP Kinases/métabolisme , Système de signalisation des MAP kinases/physiologie , Tumeurs du pancréas/métabolisme , Récepteur IGF de type 1/métabolisme , Animaux , Apoptose/effets des médicaments et des substances chimiques , Autophagie/effets des médicaments et des substances chimiques , Carcinome du canal pancréatique/traitement médicamenteux , Carcinome du canal pancréatique/anatomopathologie , Lignée cellulaire tumorale , Synergie des médicaments , Antienzymes/pharmacologie , Extracellular Signal-Regulated MAP Kinases/antagonistes et inhibiteurs , Glycolyse/effets des médicaments et des substances chimiques , Cellules HEK293 , Humains , Hydroxychloroquine/pharmacologie , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Mâle , Souris de lignée C57BL , Tumeurs du pancréas/traitement médicamenteux , Tumeurs du pancréas/anatomopathologie , Phosphorylation/effets des médicaments et des substances chimiques , Pyrazoles/pharmacologie , Récepteur IGF de type 1/antagonistes et inhibiteurs , Triazines/pharmacologie , Tests d'activité antitumorale sur modèle de xénogreffe/méthodesRÉSUMÉ
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.
Sujet(s)
Tumeurs du tronc cérébral , Gliome , Immunothérapie adoptive , Récepteur IGF de type 1 , Récepteur à l'insuline , Tumeurs du tronc cérébral/anatomopathologie , Enfant , Gliome/traitement médicamenteux , Gliome/génétique , Gliome/anatomopathologie , Humains , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteur à l'insuline/antagonistes et inhibiteurs , Lymphocytes T/métabolismeRÉSUMÉ
PURPOSE: Our understanding of thyroid-associated ophthalmopathy (TAO, A.K.A Graves' orbitopathy, thyroid eye disease) has advanced substantially, since one of us (TJS) wrote the 2010 update on TAO, appearing in this journal. METHODS: PubMed was searched for relevant articles. RESULTS: Recent insights have resulted from important studies conducted by many different laboratory groups around the World. A clearer understanding of autoimmune diseases in general and TAO specifically emerged from the use of improved research methodologies. Several key concepts have matured over the past decade. Among them, those arising from the refinement of mouse models of TAO, early stage investigation into restoring immune tolerance in Graves' disease, and a hard-won acknowledgement that the insulin-like growth factor-I receptor (IGF-IR) might play a critical role in the development of TAO, stand out as important. The therapeutic inhibition of IGF-IR has blossomed into an effective and safe medical treatment. Teprotumumab, a ß-arrestin biased agonist monoclonal antibody inhibitor of IGF-IR has been studied in two multicenter, double-masked, placebo-controlled clinical trials demonstrated both effectiveness and a promising safety profile in moderate-to-severe, active TAO. Those studies led to the approval by the US FDA of teprotumumab, currently marketed as Tepezza for TAO. We have also learned far more about the putative role that CD34+ fibrocytes and their derivatives, CD34+ orbital fibroblasts, play in TAO. CONCLUSION: The past decade has been filled with substantial scientific advances that should provide the necessary springboard for continually accelerating discovery over the next 10 years and beyond.
Sujet(s)
Anticorps monoclonaux humanisés/pharmacologie , Ophtalmopathie basedowienne , Récepteur IGF de type 1 , Animaux , Auto-immunité , Modèles animaux de maladie humaine , Ophtalmopathie basedowienne/traitement médicamenteux , Ophtalmopathie basedowienne/immunologie , Ophtalmopathie basedowienne/anatomopathologie , Humains , Souris , Orbite/immunologie , Orbite/anatomopathologie , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteur IGF de type 1/immunologieRÉSUMÉ
As a hallmark of cancer, angiogenesis plays a pivotal role in carcinogenesis. However, the correlation between angiogenesis and the evolution of BRAFV600E kinase inhibitorâacquired resistance is still poorly understood. In this study, we reported that the molecular signatures of angiogenesis were enriched in early on-treated biopsies but not in disease-progressed biopsies. The process of drug resistance development was accompanied by the remodeling of vascular morphology, which was potentially manipulated by tumor-secreted proangiogenic factors. Further transcriptomic dissection indicated that tumor-secreted IGF1 drove the vascular remodeling by activating the IGF1/IGF1R axis on endothelial cells and sustained the prompt regrowth of resistant tumor. Blockade of IGF1R with small molecules at an early stage of response disrupted vascular reconstruction and subsequently delayed tumor relapse. Our findings not only showed the correlation between IGF1-mediated tumor vascular remodeling and the development of acquired resistance to BRAFV600E kinase inhibitor but also provided a potential therapeutic strategy for the prevention of tumor relapse in clinical application.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Facteur de croissance IGF-I/métabolisme , Mélanome/traitement médicamenteux , Récidive tumorale locale/prévention et contrôle , Tumeurs cutanées/traitement médicamenteux , Animaux , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Biopsie , Lignée cellulaire tumorale , Modèles animaux de maladie humaine , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Cellules endothéliales , Femelle , Humains , Mélanome/génétique , Mélanome/anatomopathologie , Souris , Souris transgéniques , Récidive tumorale locale/anatomopathologie , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/génétique , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteur IGF de type 1/métabolisme , Tumeurs cutanées/génétique , Tumeurs cutanées/anatomopathologie , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Remodelage vasculaire/effets des médicaments et des substances chimiques , Vémurafénib/pharmacologie , Vémurafénib/usage thérapeutiqueRÉSUMÉ
Thyroid-associated ophthalmopathy (TAO) represents a disfiguring and potentially blinding autoimmune component of Graves' disease. It appears to be driven, at least in part, by autoantibodies targeting the thyrotropin receptor (TSHR)/insulin-like growth factor I receptor (IGF-IR) complex. Actions mediated through either TSHR or IGF-IR are dependent on IGF-IR activity. CD34+ fibrocytes, monocyte lineage cells, reside uniquely in the TAO orbit, where they masquerade as CD34+ orbital fibroblasts. Fibrocytes present antigens to T cells through their display of the major histocompatibility complex class II (MHC II) while providing costimulation through B7 proteins (CD80, CD86, and programmed death-ligand 1 [PD-L1]). Here, we demonstrate that teprotumumab, an anti-IGF-IR inhibitor, attenuates constitutive expression and induction by the thyroid-stimulating hormone of MHC II and these B7 members in CD34+ fibrocytes. These actions are mediated through reduction of respective gene transcriptional activity. Other IGF-IR inhibitors (1H7 and linsitinib) and knocking down IGF-IR gene expression had similar effects. Interrogation of circulating fibrocytes collected from patients with TAO, prior to and following teprotumumab treatment in vivo during a phase 2 clinical trial, demonstrated reductions in cell-surface MHC II and B7 proteins similar to those found following IGF-IR inhibitor treatment in vitro. Teprotumumab therapy reduces levels of interferon-γ and IL-17A expression in circulating CD4+ T cells, effects that may be indirect and mediated through actions of the drug on fibrocytes. Teprotumumab was approved by the US Food and Drug Administration for TAO. Our current findings identify potential mechanisms through which teprotumumab might be eliciting its clinical response systemically in patients with TAO, potentially by restoring immune tolerance.
Sujet(s)
Fibroblastes , Ophtalmopathie basedowienne/métabolisme , Récepteur IGF de type 1/antagonistes et inhibiteurs , Anticorps monoclonaux humanisés/pharmacologie , Autoanticorps/métabolisme , Cellules cultivées , Cytokines/métabolisme , Fibroblastes/effets des médicaments et des substances chimiques , Fibroblastes/immunologie , Fibroblastes/métabolisme , Humains , Récepteur TSH/métabolismeRÉSUMÉ
BACKGROUNDThe loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC.METHODSA human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion.RESULTSXenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs).CONCLUSIONThe elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.TRIAL REGISTRATIONClinicalTrials.gov (NCT03906253).FUNDINGNational Institutes of Health, Veterans Administration.
Sujet(s)
Kératose actinique/prévention et contrôle , Thérapie laser/méthodes , Vieillissement de la peau/effets des radiations , Tumeurs cutanées/prévention et contrôle , Sujet âgé , Sujet âgé de 80 ans ou plus , Animaux , Femelle , Humains , Mâle , Souris , Adulte d'âge moyen , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteur IGF de type 1/physiologie , Rayons ultravioletsRÉSUMÉ
OBJECTIVE: Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such a family of viral insulin-like peptides (VILPs). We sought to advance the chemical methods in synthesis to explore the structure-function relationship within these VILPs, and the molecular basis for differential biological activities relative to human IGF-1 and insulin. METHODS: Optimized chemical methods in synthesis were established for a set of VILPs and related analogs. These modified forms included the substitution of select VILP chains with those derived from human insulin and IGF-1. Each peptide was assessed in vitro for agonism and antagonism at the human insulin and the human insulin-like growth factor 1 receptor (IGF-1R). RESULTS: We report here that one of these VILPs, lymphocystis disease virus-1 (LCDV1)-VILP, has the unique property to be a potent and full antagonist of the IGF-1R. We demonstrate the coordinated importance of the B- and C-chains of the VILP in regulating this activity. Moreover, mutation of the glycine following the first cysteine in the B-chain of IGF-1 to serine, in concert with substitution to the connecting peptide of LCDV1-VILP, converted native IGF-1 to a high potency antagonist. CONCLUSIONS: The results reveal novel aspects in ligand-receptor interactions at the IGF-1 receptor and identify a set of antagonists of potential medicinal importance.
Sujet(s)
Iridoviridae/composition chimique , Neuropeptides/pharmacologie , Récepteur IGF de type 1/antagonistes et inhibiteurs , Humains , Neuropeptides/composition chimique , Récepteur IGF de type 1/métabolismeRÉSUMÉ
Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.
Sujet(s)
Récepteur IGF de type 1/métabolisme , Sarcomes/anatomopathologie , Anticorps monoclonaux/usage thérapeutique , Voie de signalisation Hippo , Humains , Inhibiteurs de protéines kinases/usage thérapeutique , Protein-Serine-Threonine Kinases/métabolisme , Protéines/métabolisme , Récepteur IGF de type 1/antagonistes et inhibiteurs , Récepteurs CXCR4/métabolisme , Famille des récepteurs Eph/métabolisme , Sarcomes/traitement médicamenteux , Sarcomes/métabolisme , Transduction du signalRÉSUMÉ
Herein we describe the design, synthesis and anticancer evaluation of a series of 2,3-dihydroimidazo[2,1-b]thiazoles as dual kinase inhibitors of IGF1R and EGFR. A series of saturated dihydroimidazo[2,1-b] thiazoles were synthesized to understand the structure-activity relationship. Further, the key modifications were performed to improve drug like properties of the series. A 2-oxa-6-azaspiro [3.3] heptane moiety was incorporated as a bioisosteric replacement of morpholine on dihydroimidazo[2,1-b] thiazole scaffold.Subsequent structure-activity relationship (SAR) studies identified several compounds with nM range of activity. The compound 18a shows promising activity, IC50 = 52 nM against IGF1R and IC50 = 35.5 nM against EGFR with descent PK profile. The identified leadshows promising activity against both wild type and the T790M mutant forms of enzymes.
Sujet(s)
Conception de médicament , Imidazoles/composition chimique , Inhibiteurs de protéines kinases/synthèse chimique , Récepteur IGF de type 1/antagonistes et inhibiteurs , Thiazoles/composition chimique , Administration par voie orale , Animaux , Sites de fixation , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tests de criblage d'agents antitumoraux , Récepteurs ErbB/antagonistes et inhibiteurs , Récepteurs ErbB/métabolisme , Période , Humains , Imidazoles/métabolisme , Imidazoles/pharmacologie , Souris , Simulation de docking moléculaire , Inhibiteurs de protéines kinases/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Récepteur IGF de type 1/métabolisme , Relation structure-activité , Thiazoles/métabolisme , Thiazoles/pharmacologieRÉSUMÉ
BACKGROUND: Pharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds on a robotized fluorescence microscopy platform to identify novel autophagy inducers. RESULTS: Here, we report the discovery of picropodophyllin (PPP) as a potent inducer of autophagic flux that acts on-target, as an inhibitor of the tyrosine kinase activity of the insulin-like growth factor-1 receptor (IGF1R). Thus, PPP lost its autophagy-stimulatory activity in cells engineered to lack IGF1R or to express a constitutively active AKT serine/threonine kinase 1 (AKT1) mutant. When administered to cancer-bearing mice, PPP improved the therapeutic efficacy of chemoimmunotherapy with a combination of immunogenic cytotoxicants and programmed cell death 1 (PDCD1, better known as PD-1) blockade. These PPP effects were lost when tumors were rendered PPP-insensitive or autophagy-incompetent. In combination with chemotherapy, PPP enhanced the infiltration of tumors by cytotoxic T lymphocytes, while reducing regulatory T cells. In human triple-negative breast cancer patients, the activating phosphorylation of IGF1R correlated with inhibited autophagy, an unfavorable local immune profile, and poor prognosis. CONCLUSION: Altogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.
Sujet(s)
Antinéoplasiques/usage thérapeutique , Autophagie/génétique , Récepteur IGF de type 1/antagonistes et inhibiteurs , Animaux , Antinéoplasiques/pharmacologie , Femelle , Humains , SourisRÉSUMÉ
PURPOSE: Insulin like growth factor receptor 1 (IGF-1R) has been documented to play a key role in radiation response, thereby offering an attractive drug target to enhance tumor sensitivity to radiotherapy. Here, we investigated wether knockdown of IGF-1R can sensitize colorectal cancer (CRC) cell lines to radiation. MATERIAL AND METHODS: Human colon carcinoma SW480 and HT-29 cells were transfected with specific small interference RNA (siRNA) to mediate IGF-1R depletion. The expression of IGF-1R mRNA and protein among transfected and untransfected cells was detected by Western blot analysis. Changes in cell proliferation and radiosensitivity were evaluated by the clonogenic survival assay. NVP-ADW742, an IGF-1R inhibitor, in combination with radiation was studied. RAD51, a measure for homologous recombination repair, and 53BP1, a maker for non-homologous end-joining (NHEJ), were determined by immunofluorescence for double-strand breaks (DSB) repair pathways. Cell cycle was also examined in the IGF-1R knockdown and IGF-1R-inhibited cells. RESULTS: CRC cell lines were selectively sensitized to radiation after siRNA-mediated IGF-1R depletion. NVP-ADW742 efficiently increases cancer cell response to radiation. Furthermore, initial formation of RAD51 foci after IR, and 53BP1 foci were significantly reduced in IGF-1R-depleted or with IGF-1R Inhibitor CRC cell lines. Lastly, IGF-1R-depleted or with IGF-1R Inhibitor caused more G2 phase cell arrest. CONCLUSION: Our findings demonstrate that depletion of IGF-1R lead to an increase in radiosensitivity in CRC.