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Both the epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) have been implicated in the development of cancers, and the increased expression of both receptors has been observed in esophageal cancer. However, the tyrosine kinase inhibitors of both receptors have thus far failed to provide clinical benefits for...
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... IC50 values against four different ESCC cells expressing variable levels of EGFR, HER2, and IGF-1R were quite similar, except for the KYSE150 and KYSE510 cells. The two cells are relatively insensitive to linsitinib (Figure 1a,b, Table 1). All the results were from three independent experiments and are expressed as the mean ± SD. ...Citations
... Previous research suggests that having had a democratic mother promotes prosocial emotions and better emotional regulation (24). Indeed, emotional regulation is crucial for responsiveness and empathy [i.e., the presence of empathic concern and perspective taking, not focused on personal distress; (10)]. ...
This study investigates the influence of family of origin on parental responsiveness toward own child, taking into account gender differences. A total of 110 triads of mothers, fathers, and their first child aged 6–10 months participated in the standardized Free Play procedure. Parental responsiveness was assessed through observational measures (using Ainsworth procedure) and self-reported scales (Parental Responsiveness Scale). Results revealed correlations between objectively assessed responsiveness and self-reported parental styles in the family of origin, separately for mothers and fathers. Among mothers having daughters, parental sensitivity (an important aspect of observationally measured responsiveness) was positively correlated with having had a liberal loving mother and a negative correlation with an autocratic mother. Cooperation (another aspect of observationally measured responsiveness) was correlated positively with having had a liberal loving mother. Meanwhile, having a liberal unloving mother predicted lover sensitivity and cooperation. Similar correlations were not observed for mothers having sons. Among fathers having daughters, both aspects of observed responsiveness were positively correlated with having had a democratic father and negatively with autocratic or liberal unloving parents. Moreover, having a liberal unloving father and autocratic mother predicted their lower responsiveness toward daughters. These findings highlight the role of family dynamics in shaping parental responsiveness and emphasize the importance of understanding these dynamics in promoting responsive parenting.
... (ii) Single-targeted therapy resistance caused by the presence of a compensatory signaling pathway. IGF-1R was found to be compensated by activation after the EGFR/HER2 signaling pathway was inhibited, so the efficacy of receptor TKIs alone was not significant, while the combination of the dual EGFR/HER2 inhibitors lapatinib and gefitinib with the IGF-1R inhibitor linsitinib, inhibited the mutual crosstalk between EGFR/ HER2 and IGF-1R, remarkably enhancing ESCC cell cycle arrest and apoptosis [113]. ...
Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half of them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote the release of cytokines and chemokines, and triggers inflammatory reactions and changes in the tumor microenvironment (TME), thereby inhibiting the immune function and causing the invasion and metastasis of ESCC. Radioresistance is the major cause of disease progression and mortality in cancer, and it is associated with heterogeneity. Therefore, a better understanding of the radioresistance mechanisms may generate more reversal strategies to improve the cure rates and survival periods of ESCC patients. We mainly summarized the possible mechanisms of radioresistance in order to reveal new targets for ESCC therapy. Then we summarized and compared the current strategies to reverse radioresistance.
... 98 The combination of immunotherapy with angiogenesis inhibitors has exhibited promising efficacy in various solid tumours [99][100][101] ; this combination deserves further investigation in the future as a burgeoning combination regimen for advanced ESCC. Besides, dual inhibition of the epidermal growth factor receptor/human epidermal growth factor receptor 2 and insulin-like growth factor 1 receptor signalling pathways showed superior anti-tumour efficacy in vitro experiments of ESCC 102 and is expected to be confirmed in clinical trials. ...
Oesophageal squamous cell carcinoma (ESCC) is a kind of malignant tumour with high invasiveness and a poor prognosis. Immunotherapy, especially immune checkpoint inhibitors (ICIs), is a rapidly growing therapeutic method that activates and enhances anti-tumour immunity to treat patients with malignancy. Several clinical trials have confirmed the efficacy of ICIs in the treatment of ESCC. ICIs have been approved for the treatment of patients with ESCC. However, only a subset of patients can obtain excellent benefits from ICI therapy. In recent years, there has been a growing interest in exploring predictive biomarkers of immunotherapy response. In this review, we highlighted the predictive biomarkers for the prognosis of ESCC patients treated with ICIs and pointed out the existing problems and the direction of future research in this field.
... Similarly, based on their highly consistent co-expression profile, the approach of dual inhibition of IGF1R and EGFR/HER2 was adopted and have shown significant success in multiple preclinical models of different cancer -viz. (i) a bi-specific (anti-IGF1R and -EGFR) antibody XGFR in pancreatic cancer (Schanzer et al. 2016), (ii) IGF1R inhibitor linsitinib with EGFR inhibitors lapatinib or gefitinib in esophageal squamous cell carcinoma (Kang et al. 2022), (iii) a ligandbased enediyne-energized bi-specific fusion protein (anti-IGF1R and -EGFR) in esophageal ) and non-small-cell lung cancer , (iv) AVE1642 (anti-IGF1R mAb) and gefitinib in HCC (Desbois-Mouthon et al. 2009), (v) ganitumab and panitumumab (anti-EGFR mAb) in advanced cancers (non-small-cell lung cancer and sarcoma) (Vlahovic et al. 2018) and (vi) ganitumab and panitumumab in metastatic colorectal cancer (Van Cutsem et al. 2014), to name a few. Interestingly, the antidiabetic 'wonder drug' metformin is reported to affect a downregulation of IGF1R and thereby enhance the efficacy of figitumumab (mAb against IGF1R) in small-cell lung cancer (Cao et al. 2015) and non-small-cell lung cancer (Cao et al. 2016). ...
Despite landmark advances in cancer treatments over the last 20 years, cancer remains the second highest cause of death worldwide, much ascribed to intrinsic and acquired resistance to the available therapeutic options. In this review, we address this impending issue, by focusing the spotlight on the rapidly emerging role of growth hormone action mediated by two intimately related tumoral growth factors - growth hormone (GH) and insulin-like growth factor 1 (IGF1). Here, we not only catalog the scientific evidences relating specifically to cancer therapy resistance inflicted by GH and IGF1, but also discuss the pitfalls, merits, outstanding questions and the future need of exploiting GH-IGF1 inhibition to tackle cancer treatment successfully.
... In several recent studies, dysregulated RTK family members were found in OSCC patients [12,13]. As 'stress-receptors' , they can receive and transmit extracellular 'harsh' messages such as warnings about low oxygen levels to the cytoplasm, and initiate the intracellular downstream signal cascade to promote the growth, invasion, metabolism, and resistance phenotype of tumour cells [14]. ...
... IGF1R, as a transmembrane glycoprotein and stress-receptor, could feel the stress outside and send these stress signals to intracellular, activating downstream pathways to regulate cell proliferation, migration, and chemotherapeutic resistance [14]. However, singletarget RTKs have been proven to be inefficient due to multiple factors, such as the negative feedback activation in other oncogenic pathways [49] and the existence of complex crosstalks between different RTK pathways [12]. Combination therapy is emerging as a superior option; for example, the HER2 inhibitor trastuzumab deruxtecan, combined with DDP, has been approved as a first-line treatment in certain specific types of cancer [50]. ...
Background:
Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application and the underlying mechanisms at play remain unclear. The aims of this study were to elucidate the role of abnormal signal transmission and metabolism in the chemoresistance of OSCC under hypoxia and to identify targeted drugs that enhance the sensitivity of DDP chemotherapy.
Methods:
Upregulated genes in OSCC were determined by RNA sequencing (RNA-seq), the Cancer Genome Atlas (TCGA) database, immunohistochemistry (IHC), real-time quantitative PCR (RT-qPCR), and western blotting (WB). The clinicopathological significance of insulin-like growth factor-I receptor (IGF1R), argininosuccinate synthetase 1 (ASS1), and pyrroline-5-carboxylate reductase 1 (PYCR1) in OSCC was analysed using tissue micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP-resistance role of IGF1R, ASS1, and PYCR1 in OSCC was investigated in vitro and in vivo.
Results:
Generally, tumour cells exist in a hypoxic microenvironment. By genomic profiling, we determined that IGF1R, as a receptor tyrosine kinase (RTK), was upregulated in OSCC under low-oxygen conditions. Clinically, enhanced IGF1R expression was associated with higher tumour stages and a poorer prognosis in OSCC patients, and its inhibitor, linsitinib, showed synergistic effects with DDP therapy in vivo and in vitro. Since oxygen-deprivation frequently lead to metabolic reprogramming, we further learned via metabolomics analysis that abnormal IGF1R pathways promoted the expression of metabolic enzymes ASS1 and PYCR1 by the transcriptional activity of c-MYC. In detail, enhanced expression of ASS1 promotes arginine metabolism for biological anabolism, whereas PYCR1 activates proline metabolism for redox balance, which maintains the proliferation ability of OSCC cells during DDP treatment under hypoxic conditions.
Conclusion:
Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under hypoxia. Linsitinib targeting IGF1R signaling may lead to promising combination therapy options for OSCC patients with DDP resistance.
... Accordingly, a number of chemotherapeutic drugs like imatinib (1; Figure S1; see supplementary file), gefitinib (2), erlotinib (3), and afatinib (4) have been introduced globally to treat this malignant disease (Abourehab et al., 2021;Yamaoka et al., 2018). The primary goal of these medications' action targets is to affect the EGFR-TK signal transduction pathway (Gaber et al., 2021;Kang et al., 2022). On the other hand, cyclin-dependent kinases (CDKs) also play a pivotal role in the regulation of the cell cycle. ...
Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C
NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 mM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.
... Gefitinib (GR) is the most common and effective chemotherapeutic agent for the management of ESCA (107). It is estimated that 60-80% of patients with advanced ESCA have elevated EGFR expression levels in the cancerous tissue (107)(108)(109), and GR can inhibit EGFR expression and thus improve the prognosis of patients with ESCA. However, GR resistance in patients with advanced ESCA has become a major limiting factor affecting long-term patient prognosis, and the mechanisms of resistance are currently unclear. ...
With advancements in sequencing technologies, an increasing number of aberrantly expressed long-non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have been identified in various types of cancer. lncRNAs and circRNAs are now well-established tumor-influencing factors in cancer, driving not only tumor proliferation and invasion, but also cancer progression, drug resistance and metastatic recurrence. The majority of lncRNAs and circRNAs influence cancer progression by targeting microRNAs (miRNAs/miRs). miR-10a and miR-10b, key members of the miR-10 family, have been shown to play important regulatory roles in cell proliferation, differentiation to cancer progression, and development. Manual evaluation and grouping according to different types of competing endogenous RNA and tumor was performed. The review outlined the current state of knowledge on the regulation of miR-10 family-related lncRNAs and circRNAs. The involvement of lncRNAs and circRNAs in the biogenesis, maturation and function of malignant tumors through the miR-10 family, and the key gene targets and signaling cascades that lncRNAs and circRNAs regulate through the miR-10 family were summarized. Based on the findings of this review, it can be hypothesized that lncRNAs and circRNAs targeting the miR-10 family may serve as diagnostic/prognostic markers and/or therapeutic targets for the management of cancer.
... From several recent studies, dysregulated receptor tyrosine kinases (RTKs) family members were found in OSCC patients [10][11]. As"stress-receptors", they can received and transmitted extracellular "harsh" message such as low oxygen to cytoplasm, and started the intracellular downstream signal cascade to cell growth, invasion, metabolism and resistant phenotype of tumor cells [12]. ...
... IGF1R as a transmembrane glycoprotein and stress-receptor, could feel the stress outside and send these stress signals to intracellular, activating downstream signaling pathways to regulate cell proliferation, migration and chemotherapeutic resistance, etc [12]. However, single-targeted RTKs had been proved ine cient due to mutiple factors, such as the negative feedback activation in other oncogenic pathways [46], complex crosstalks between different RTK pathways [10]. Combination therapy is emerging as a superior option, for example, HER2 inhibitor trastuzumab deruxtecan, combined with DDP has been approved as a rst-line treatment in certain speci c types of cancer [47]. ...
Background & Aims:
Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application, and the underlying mechanisms remain unclear. The aims of this study is to elucidate the role of abnormal signal transmission and metabolism in chemoresistance of OSCC under oxygen-deprived microenvironment, and try to find targeted drugs that enhance the sensitivity of DDP chemotherapy.
Methods:
Upregulated genes in OSCCs were determined by RNA-seq, public database, IHC, rt-qPCR and Western blotting (WB). The clinicopathological significance of IGF1R, ASS1, PYCR1 in OSCC were analyzed using Tissue Micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP resistance role of IGF1R, ASS1, PYCR1 in OSCC was investigated in vitro and in vivo.
Results:
Generally, tumor cells are in a hypoxic microenvironment. By genomic profiling, we
identified IGF1R as one of RTKs, were upregulated in OSCCs under low oxygen condition. Clinically, enhanced IGF1R expression was associated with higher stages and poor prognosis in OSCC patients, and it’s inhibitor linsitinib, showed synergistic effects on DDP therapy in vivo and in vitro.Since hypoxia conditions frequently lead to metabolic reprogramming, we further integrated metabolomic analysis to find that abnormal IGF1R pathways promoted the expression of metabolic enzymes argininosuccinate synthetase 1 (ASS1) and pyrroline-5-carboxylate reductase 1 (PYCR1) via transcriptional activity of cMYC. Deeply, enhanced expression of ASS1 promoted arginine metabolism for biological anabolism, whereas PYCR1 activated proline metabolism for redox balance, which maintained the proliferation ability of OSCC cells during DDP treatment under hypoxia condition.
Conclusions:
Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under low oxygen conditions. Linsitinib targeting IGF1R signaling may provides promising combination therapy options for OSCC patients with DDP resistance.
The journey of cancer development is a multifaceted and staged process. The array of treatments available for cancer varies significantly, dictated by the disease's type and stage. Cancer-associated fibroblasts (CAFs), prevalent across various cancer types and stages, play a pivotal role in tumor genesis, progression, metastasis, and drug resistance. The strategy of concurrently targeting cancer cells and CAFs holds great promise in cancer therapy. In this review, we focus intently on CAFs, delving into their critical role in cancer's progression. We begin by exploring the origins, classification, and surface markers of CAFs. Following this, we emphasize the key cytokines and signaling pathways involved in the interplay between cancer cells and CAFs and their influence on the tumor immune microenvironment. Additionally, we examine current therapeutic approaches targeting CAFs. This article underscores the multifarious roles of CAFs within the tumor microenvironment and their potential applications in cancer treatment, highlighting their importance as key targets in overcoming drug resistance and enhancing the efficacy of tumor therapies.
The discovery of therapeutic molecules is fundamentally a multi-objective optimization problem. One formulation of the problem is to identify molecules that simultaneously exhibit strong binding affinity for a target protein, minimal off-target interactions, and suitable pharmacokinetic properties. Inspired by prior work that uses active learning to accelerate the identification of strong binders, we implement multi-objective Bayesian optimization to reduce the computational cost of multi-property virtual screening and apply it to the identification of ligands predicted to be selective based on docking scores to on- and off-targets. We demonstrate the superiority of Pareto optimization over scalarization across three case studies. Further, we use the developed optimization tool to search a virtual library of over 4M molecules for those predicted to be selective dual inhibitors of EGFR and IGF1R, acquiring 100% of the molecules that form the library's Pareto front after exploring only 8% of the library. This workflow and associated open source software can reduce the screening burden of molecular design projects and is complementary to research aiming to improve the accuracy of binding predictions and other molecular properties.
