scholarly journals Disrupting Insulin and IGF Receptor Function in Cancer

2021 ◽  
Vol 22 (2) ◽  
pp. 555
Author(s):  
Jingran Cao ◽  
Douglas Yee
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Laboratory Data ◽  
Standard Of Care ◽  
Phase Iii ◽  
Type I ◽  
Phase Iii Clinical Trials ◽  
Igf System ◽  
Type I Igf Receptor ◽  
Igf Receptor

The insulin and insulin-like growth factor (IGF) system plays an important role in regulating normal cell proliferation and survival. However, the IGF system is also implicated in many malignancies, including breast cancer. Preclinical studies indicate several IGF blocking approaches, such as monoclonal antibodies and tyrosine kinase inhibitors, have promising therapeutic potential for treating diseases. Uniformly, phase III clinical trials have not shown the benefit of blocking IGF signaling compared to standard of care arms. Clinical and laboratory data argue that targeting Type I IGF receptor (IGF1R) alone may be insufficient to disrupt this pathway as the insulin receptor (IR) may also be a relevant cancer target. Here, we review the well-studied role of the IGF system in regulating malignancies, the limitations on the current strategies of blocking the IGF system in cancer, and the potential future directions for targeting the IGF system.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

Glucose regulation of the IGF response system in chondrocytes: induction of an IGF-I-resistant state

1999 ◽  
Vol 276 (4) ◽  
pp. R1164-R1171 ◽  
Author(s):  
K. M. Kelley ◽  
T. R. Johnson ◽  
J. Ilan ◽  
R. W. Moskowitz
Keyword(s):  
Glucose Concentration ◽  
Northern Analysis ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels ◽  
Receptor Mrna ◽  
Response System ◽  
Type I Igf Receptor ◽  
Igf I ◽  
Igf Receptor

Nonresponsiveness to the growth-stimulatory actions of insulin-like growth factor (IGF)-I in chondrocytes has been reported in a number of disease states associated with impaired glucose metabolism. Primary rabbit chondrocytes were investigated for changes in their IGF response system [type-I IGF receptor and IGF-binding protein (IGFBP) expression] and in their ability to mount a synthetic response to IGF-I [as35S-labeled proteoglycan ([35S]PG) production] in media containing varying ambient glucose concentrations. Whereas basal [35S]PG synthetic rate was unaffected by glucose concentration, synthetic responsiveness to IGF-I was lost in media containing <5 mmol/l glucose or in media containing a “diabetic” glucose concentration (25 mmol/l). IGFBP expression, as measured by Northern analysis of mRNA levels and Western ligand blotting of secreted protein levels, was not significantly altered in the different glucose media, nor were there any differences in the cell surface localization of IGFBPs as assessed by affinity cross-linking with 125I-labeled IGF-I, suggesting that IGFBPs do not induce the IGF-I resistance. The nonresponsiveness to IGF-I in reduced glucose occurred with 25–50% reductions in steady-state levels of IGF type-I receptor mRNA and protein. A significant correlation between IGF receptor mRNA level and synthetic response to IGF-I was observed between 0 and 10 mmol/l glucose concentrations, suggesting that the loss of responsiveness in reduced glucose is manifested at the level of transcription and/or receptor mRNA stability. In contrast, nonresponsiveness to IGF-I in chondrocytes in diabetic glucose concentrations occurred without changes in receptor mRNA and protein levels, suggesting that IGF-I resistance was due to post-ligand-binding receptor defects. It is proposed that IGF-I resistance in chondrocytes subjected to inappropriate glucose levels may constitute an important pathogenic mechanism in degenerative cartilage disorders.

scholarly journals Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study)

2016 ◽  
Vol 76 (5) ◽  
pp. 811-820 ◽  
Author(s):  
Thomas Bardin ◽  
Robert T Keenan ◽  
Puja P Khanna ◽  
Jeff Kopicko ◽  
Maple Fung ◽  
...  
Keyword(s):  
Adverse Events ◽  
Laboratory Data ◽  
Standard Of Care ◽  
Phase Iii ◽  
Controlled Study ◽  
Inadequate Response ◽  
Double Blind ◽  
Significant Treatment ◽  
End Points ◽  
Registration Number

ObjectivesDetermine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.MethodsPatients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data.ResultsPatients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively.ConclusionLesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.Trial registration numberNCT01493531.

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

Involvement of phenylalanine 23 in the binding of IGF-1 to the insulin and type I IGF receptor

1996 ◽  
Vol 66 (3) ◽  
pp. 191-196 ◽  
Author(s):  
Darren R. Hodgson ◽  
Felicity E.B. May ◽  
Bruce R. Westley
Keyword(s):  
Type I ◽  
Type I Igf Receptor ◽  
Igf Receptor

Detection and downregulation of type I IGF receptor expression by antibody-conjugated quantum dots in breast cancer cells

2008 ◽  
Vol 114 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Hua Zhang ◽  
Deepali Sachdev ◽  
Chun Wang ◽  
Allison Hubel ◽  
Martine Gaillard-Kelly ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Quantum Dots ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Receptor Expression ◽  
Type I ◽  
Type I Igf Receptor ◽  
Igf Receptor

Type-I insulin-like growth factor receptor gene expression in the chick. Developmental changes and the effect of selection for increased growth on the amount of receptor mRNA

1994 ◽  
Vol 12 (1) ◽  
pp. 3-12 ◽  
Author(s):  
D G Armstrong ◽  
C O Hogg
Keyword(s):  
Rnase Protection Assay ◽  
Reaction Medium ◽  
Type I ◽  
Rnase Protection ◽  
Receptor Mrna ◽  
Type I Igf Receptor ◽  
Mrna Transcripts ◽  
Actin Mrna ◽  
Igf Receptor ◽  
Selection For

ABSTRACT An RNase protection assay is described that allowed the quantitative analysis of chicken type-I IGF receptor mRNA transcripts. The transcripts were measured in extracts of total nucleic acid (TNA) and, under the hybridization conditions described, protected probes of the expected size were obtained. The RNA-RNA hybrids could be quantified in the presence of at least a 1000-fold molar excess of DNA containing sequences which were complimentary to the RNA probe. The amount of protected probe was linearly related to the amount of TNA in the hybridization reaction medium, and this allowed the results to be expressed in the form of mRNA molecules/cell. Type-I IGF receptor mRNA transcripts were detected in all the tissues examined from a 20day-old chick embryo. Their amount ranged from 5 to 24 molecules/cell, in the order liver<breast muscle<leg muscle<heart<brain. The amount of receptor mRNA was 65- to 300-fold less than that of β-actin mRNA. The quantity of type-I IGF receptor mRNA varied significantly throughout embryonic and post-hatch development. Maximum amounts were measured in 21-day-old embryos (a two- to fourfold increase relative to 16-day-old embryos). Thereafter the amount of receptor mRNA decreased, during the 4-week period after hatching, to levels which were significantly lower than that observed in 16-day-old embryos. Throughout the period of embryonic and post-hatch development described here the amount of β-actin mRNA remained constant, indicating that the changes in the quantity of receptor mRNA were due to specific mechanisms acting directly on the steady-state levels of type-I IGF receptor mRNA. Selection for increased growth had no effect on the amount of type-I IGF receptor mRNA. The result was the same when expressed either as molecules/cell or as a percentage of β-actin mRNA.

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