Treatment Of Esophageal Squamous Cell Carcinoma Research Articles

Unraveling the tumor microenvironment of esophageal squamous cell carcinoma through single-cell sequencing: A comprehensive review.

Esophageal squamous cell carcinoma (ESCC) is a highly heterogeneous and aggressive malignancy. The progression, invasiveness, and metastatic potential of ESCC are shaped by a multitude of cells within the tumor microenvironment (TME), including tumor cells, immune cells, endothelial cells, as well as fibroblasts and other cell types. Recent advancements in single-cell sequencing technologies have significantly enhanced our comprehension of the diverse landscape of ESCC. Single-cell multi-omics technology, particularly single-cell transcriptome sequencing, have shed light on the expression profiles of individual cells and the molecular characteristics of distinct tumor cell populations. This review summarizes the latest literature on single-cell research in the field of ESCC, aiming to elucidate the heterogeneity of tumor cells, immune cells, and stromal cells at the single-cell level. Furthermore, it explores the impact of cellular interactions within the TME on the progression of ESCC. By compiling a comprehensive overview of single-cell omics research on ESCC, this article aims to enhance our understanding of ESCC diagnosis and treatment by elucidating the intricate interplay within the TME. It explores the cellular composition, spatial arrangement, and functional attributes of the ESCC TME, offering potential therapeutic targets and biomarkers for personalized treatment strategies.

Efficacy, safety and DNA methylation analysis of cadonilimab combined with taxane and cisplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Updated results from an open-label, multicenter phase II trial (AK104-IIT-014).

463 Background: Immune checkpoint inhibitors combined with chemotherapy had become the first-line standard treatment for advanced ESCC and cadonilimab, as a bispecific antibody simultaneously targeting PD-1 and CTLA-4, may further boost anti-tumor activity with a satisfied safety profile. Here, we present the updated data for the safety and efficacy of cadonilimab combination therapy as the first-line treatment in advanced ESCC. The correlation between DNA methylation and clinical response was also investigated. Methods: Treatment-naïve patients (pts) with unresectable locally advanced or metastatic ESCC were enrolled. Cadonilimab (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m 2 , iv, d1, q3w) and cisplatin (65 to 75 mg/m 2 , iv, d1, q3w) were administrated for up to 6 cycles, then Cadonilimab (10mg/kg, iv, d1, q3w) monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for methylation level sequencing. Results: As of September 20, 2024, 43 pts were enrolled with a median age of 61 years (range 44-75), 81.4% were male, 39.5% had PD-L1 CPS≥10 and 95.3% had metastatic diseases. All pts were evaluable for safety and efficacy. The ORR was 81.4% (95%Cl: 66.1%-91.1%) and DCR was 97.7% (95%Cl: 86.2%-99.9%). The median PFS (mPFS) was 7.05 months (mo) (95%Cl: 5.86-8.24) and OS analysis was immature. In the PD-L1 CPS≥10 pts, the ORR was 100.0% (95%Cl: 77.1%-100.0%) and mPFS was 7.05 mo (95%Cl: 5.19-8.91). In the PD-L1 CPS＜10 pts, the ORR was 77.3% (95%Cl: 54.2%-91.3%) and mPFS was 7.05 mo (95%Cl: 5.87-8.24). Six hyper-methylated CpG sites, EPTIN9、PKNOX2、DLEU7、SOX7、CNRIP1 and LINC00554 might be the candidate biomarkers as the mean pretreatment methylation levels were significantly higher in the PR pts than those in the non-PR pts (p=7.8×10 -7 ). Grade 3-4 treatment-related adverse events (TRAEs) were reported in 44.2% (19/43) pts, mainly including neutropenia (25.6%), leukopenia (9.3%) and hyponatremia (7.0%). The infusion-related reactions (IRR) occurred in 14.0% (6/43) and grade ≥3 IRR occurred in 4.7% (2/43) pts. 7 pts discontinued cadonilimab administration due to TRAEs. Conclusions: The updated results suggested that bispecific antibody cadonilimab combined with taxane and cisplatin as first-line treatment continued to show encouraging anti-tumor activity and manageable safety in pts with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes. Clinical trial information: NCT05522894 .

Fruquintinib plus camrelizumab combined with paclitaxel liposome and nedaplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, phase II clinical trial.

445 Background: Camrelizumab in combination with chemotherapy has become a standard of care for the first-line treatment of advanced ESCC. Previous studies have indicated synergistic effect of fruquintinib in combination with chemotherapy or immunotherapy. Hence, we conducted a phase II trial to evaluate the efficacy and safety of fruquintinib plus camrelizumab, paclitaxel liposome, and nedaplatin as a first-line therapy for advanced ESCC. Methods: This is a single-arm, phase II study consisting of a dose-finding and a dose-expansion phase. A total of 33~36 patients aged 18~80 years with previously untreated advanced ESCC and an ECOG PS of 0-2 were planned to be enrolled. The dose-finding phase followed a 3+3 approach in order to determine the recommended phase II dose (RP2D) of fruquintinib for dose expansion. Patients received fruquintinib (3 mg, 4 mg, and 5 mg once daily on days 1-14, starting at 4 mg) orally, plus intravenous camrelizumab 200 mg d1, paclitaxel liposome 135 mg/m 2 d1, and nedaplatin 70 mg/m 2 d1, 21 days as one cycle. A maximum of 6 cycles was conducted, followed by maintenance therapy with fruquintinib in combination with camrelizumab. The primary endpoint was objective response rate (ORR, RECIST 1.1). Secondary endpoints included RP2D, disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). Results: As of August 24, 2024, 11 patients (9 males) were enrolled with a median age of 66 years (range 50-76). All patients had distant metastases, and the median number of sites of metastasis was 2 (range 1-5). In the dose-finding phase, 3 patients were treated with 4 mg of fruquintinib, and 6 patients were treated with 5 mg of fruquintinib. No dose-limiting toxicities (DLTs) were observed. Thus, the RP2D of fruquintinib was established as 5 mg once daily on days 1-14, 21 days as one cycle. Of the 7 evaluable patients, 6 achieved partial response, and 1 had stable disease. The ORR was 85.7% (95% CI 42.1%-99.6%), and the DCR was 100.0% (95% CI: 59.0%-100.0%). The median PFS was not reached. The most common treatment-related adverse events (TRAEs) were anemia (7/11), hypercholesterolemia (6/11), hypoalbuminemia (5/11), oral mucositis (5/11), hematuria (4/11), hypertension (4/11), fatigue (4/11), constipation (3/11), and neutropenia (3/11). Grade 3 TRAEs were identified in 2 patients, including oral mucositis (2/11), and anemia (1/11). No treatment-related serious adverse events (SAEs) or deaths occurred. Conclusions: The combination of fruquintinib, camrelizumab, paclitaxel liposome, and nedaplatin demonstrated significant efficacy and manageable toxicity profiles as a first-line treatment for advanced ESCC, suggesting a potential new treatment strategy. Clinical trial information: NCT06010212 .

Use of immune repertoire sequencing analysis to detect differences in treatment responses for advanced esophageal squamous cell carcinoma treated with camrelizumab and platinum-based chemotherapy.

488 Background: The study evaluated the efficacy and safety of camrelizumab combined with platinum-based chemotherapy (platinum plus paclitaxel [TP] or fluorouracil [FP] agents) as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC), and explored potential biomarkers for treatment response using immune repertoire (IR) sequencing. Methods: In this multi-center, prospective cohort study, advanced ESCC patients were treated with camrelizumab and TP or FP chemotherapy. Primary outcome was 1-year progression free survival (PFS). Secondary outcomes included 1-year overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Patients were categorized based on their treatment responses into the non-ORR and ORR groups. IR sequencing was exploratorily performed on the peripheral blood mononuclear cells from 15 patients in each group. Results: From June 2020 to April 2023, 88 out of 98 screened patients were enrolled, with a median follow-up of 15.9 months. The 1-year PFS was 56.8%, OS was 68.2%, ORR was 64.8%, and DCR was 91.1%. Most treatment-related adverse events were grade 1-2, though 12.5% experienced grade ≥3 toxicities. The FP regimen's efficacy was comparable to the TP regimen. The analysis of the complementarity-determining region 3 polypeptide sequences revealed significant differences in amino acid composition between the non-ORR and ORR groups in T-cell receptor beta-chain (TRB) and immunoglobulin heavy chain (IGH) repertoire. Furthermore, the ORR group exhibited a more concentrated distribution of clones within TRB. Two V genes (TRBV29-1 and TRBV4-1) and one J gene (TRBJ1-3) in the TRB region, along with six V genes (IGHV1-45, IGHV3-20, IGHV3-48, IGHV3-49, IGHV4-4, and IGHV5-51) in the IGH region, were differentially expressed between the two groups. Conclusions: Camrelizumab with platinum-based chemotherapy is effective and well-tolerated as first-line treatment in advanced ESCC. IR sequencing may provide insights into the underlying mechanisms influencing treatment response. Clinical trial information: ChiCTR2000037942. Objective response and disease response. Efficacy evaluation Total (N=88) Camrelizumab plus T（n=69） Camrelizumab plus FP (n=19) p 1-year PFS rate 50/88 (56.8%) 39/69 (56.5%) 11/19 (57.9%) 1.000 1-year OS rate 60/88 (68.2%) 47/69 (68.1%) 13/19 (68.4%) 1.000 ORR 57/88 (64.8%) 43/69 (62.3%) 11/19 (57.9%) 0.793 DCR 81/88 (91.1%) 63/69 (91.3%) 15/19 (79.0%) 0.213 ORR group, n (%) 54/88 (61.4%) 43/69 (62.3%) 11/19 (57.89%) 0.793 Non-ORR Group, n (%) 34/88 (38.6%) 26/69 (37.7%) 8/19 (42.1%) 1.000 2-year PFS rate 38/88 (43.2%) 30/69 (43.5%) 8/19 (42.1%) 1.000 2-year OS rate 42/88 (47.7%) 33/69 (47.8%) 9/19 (47.4%) 1.000 *p<0.05, a statistically difference.

Response characteristics of tislelizumab (TIS) plus chemotherapy (chemo) in first-line (1L) treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC): A post hoc analysis of RATIONALE-306.

413 Background: The global phase 3 RATIONALE-306 study (NCT03783442) demonstrated superior OS, PFS, ORR and manageable safety profile of TIS + chemo as 1L treatment of ESCC, which was well maintained at 3 years. This post-hoc analysis aims to explore the response characteristics of responders in TIS + chemo arm from RATIONALE-306. Methods: Advanced or metastatic ESCC patients (pts) were randomly assigned (1:1) to receive 1L TIS + chemo or placebo + chemo. Assessments of tumor response were done every 6 weeks for the first 48 weeks, then every 9 weeks thereafter per RECIST v1.1. Time to response (TTR), depth of response (DpR) and time to maximum response (TTMR) were assessed in responders (pts who achieved CR or PR). TTR was defined as the time from randomization to the first occurrence of a CR or PR, DpR as the percentage of maximal tumor reduction from the baseline of target lesion sum of diameters, and TTMR as the time from randomization to the maximum tumor shrinkage. Results: As of 24 November 2023, 207 pts (68.3% of the ITT population) in the TIS + chemo arm achieved responses, with a median TTR of 6.1 weeks (range: 3.3 - 101.3). First response was detected in 64.7% of responders within 8 weeks, 22.2% between > 8 and ≤ 14 weeks, and 13.0% after 14 weeks; the median OS was 21.8, 23.1 and 29.0 mos, respectively in pts within the three TTR categories, and the median OS post first response was 21.3, 21.3 and 23.2 mos (Table). DpR > 30% to ≤ 50%, > 50% to ≤ 80%, and > 80% to ≤ 100% was observed in 29.8%, 50.2% and 20.0% of responders, respectively, and the median OS was 16.1, 23.7, and 34.5 mos. The median TTMR was 19 weeks (range: 3.3 - 201.0), with 32.7% of responders achieved maximum response within 14 weeks, 34.6% between > 14 and ≤ 28 weeks, and 32.7% after 28 weeks, respectively. Median OS of pts with the three TTMR categories was 14.3, 17.4, and 39.9 mos, respectively, and median OS post-maximum response was 12.6, 14.3, and 24.8 mos. Conclusions: In the TIS + chemo arm, 64.7% of responders achieved response within 8 weeks, while still 35.2% of responders achieved response at later tumor assessments, and the OS benefits were comparable between early responders and late responders. Responders with deeper tumor response and/or longer TTMR tended to have longer OS. Clinical trial information: NCT03783442 . Cutoff Patients, n (%) OS, median (95% CI), mos OS from response*, median (95% CI), mos TTR > 0 to ≤ 8w 134 (64.7) 21.8 (16.3, 25.0) 21.3 (16.0, 24.5) > 8 to ≤ 14 w 46 (22.2) 23.1 (16.3, 26.0) 21.3 (14.4, 24.3) > 14w 27 (13.0) 29.0 (20.4, NA) 23.2 (15.9, NA) DpR > 30% to ≤ 50% 61 (29.8) 16.1 (13.2, 20.8) \ > 50% to ≤ 80% 103 (50.2) 23.7 (19.6, 25.6) \ > 80% to ≤ 100% 41 (20.0) 34.5 (23.7, NA) \ TTMR > 0 to ≤ 14w 67 (32.7) 14.3 (8.7, 17.6) 12.6 (8.1, 15.4) > 14 to ≤ 28w 71 (34.6) 17.4 (15.8, 24.1) 14.3 (11.8, 20.1) > 28w 67 (32.7) 39.9 (28.6, NA) 24.8 (17.5, 39.4) *From first response for TTR, and from maximum response for TTMR.

Activin A receptor type 1C single nucleotide polymorphisms associated with esophageal squamous cell carcinoma risk in Chinese population.

Transforming growth factor-β (TGF-β) superfamily plays an important role in tumor progression and metastasis. Activin A receptor type 1C (ACVR1C) is a TGF-β type I receptor that is involved in tumorigenesis through binding to different ligands. To evaluate the correlation between single nucleotide polymorphisms (SNPs) of ACVR1C and susceptibility to esophageal squamous cell carcinoma (ESCC) in Chinese Han population. In this hospital-based cohort study, 1043 ESCC patients and 1143 healthy controls were enrolled. Five SNPs (rs4664229, rs4556933, rs77886248, rs77263459, rs6734630) of ACVR1C were assessed by the ligation detection reaction method. Hardy-Weinberg equilibrium test, genetic model analysis, stratified analysis, linkage disequilibrium test, and haplotype analysis were conducted. Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC, and those with rs77886248 TA mutant were related with higher risk, especially in older male smokers. In the haplotype analysis, ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC, while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC. ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC, which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.

RTN4IP1 Contributes to ESCC via Regulation of Amino Acid Transporters.

Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases. The lack of effective therapeutic targets makes it difficult to improve the overall survival of patients with ESCC. Reticulon 4 Interacting Protein 1 (RTN4IP1) is a novel mitochondrial oxidoreductase. Here, a notable upregulation of RTN4IP1 is demonstrated, which is associated with poor survival in patients with ESCC. RTN4IP1 depletion impairs cell proliferation and induces apoptosis of ESCC cells. Furthermore, c-Myc regulates RTN4IP1 expression via iron regulatory protein 2 (IRP2) at the post-transcriptional level. Mechanistically, RTN4IP1 mRNA harbors functional iron-responsive elements (IREs) in the 3' UTR, which can be targeted by IRP2, resulting in increased mRNA stability. Finally, RTN4IP1 depletion abrogates amino acid uptake and induces amino acid starvation via downregulation of the amino acid transporters SLC1A5, SLC3A2, and SLC7A5, indicating a possible pathway through which RTN4IP1 contributes to ESCC carcinogenesis and progression. In vivo studies using cell-derived xenograft and patient-derived xenograft mouse models as well as a 4-nitroquinoline 1-oxide-induced ESCC model in esophageal-specific Rtn4ip1 knockout mice demonstrate the essential role of RTN4IP1 in ESCC development. Thus, RTN4IP1 emerges as a key cancer-promoting protein in ESCC, suggesting therapeutic RTN4IP1 suppression as a promising strategy for ESCC treatment.

Macrophage Infiltration and ITGB2 Expression in ESCC: A Novel Correlation.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and lethal malignancies worldwide. Despite progress in immunotherapy for cancer treatment, its application and efficacy in ESCC remain limited. Therefore, there is an ongoing need to explore potential molecules and therapeutic strategies related to tumor immunity in ESCC. In this study, we integrated high-throughput sequencing data, gene chip data, single-cell sequencing data, and various bioinformatics analysis methods along with experimental approaches to identify key genes involved in immune infiltration in ESCC and investigate their relationship with immune cell development, as well as the potential of these key genes in immunotherapy. We discovered and validated a positive correlation between macrophage infiltration and ITGB2 expression in ESCC. ITGB2 is overexpressed in ESCC and has potential as a prognostic biomarker for the disease. We present for the first time the finding that the expression of ITGB2 in infiltrating macrophages increases as these macrophages polarize toward a tumor-promoting phenotype in ESCC. Moreover, during the progression of ESCC, ITGB2 expression in infiltrating macrophages is upregulated. The higher the expression of ITGB2, the more feasible it is to target macrophages. Additionally, we found that evaluating immune therapy responses in ESCC patients through ITGB2 expression is a viable approach. Furthermore, we identified three miRNAs associated with abnormal ITGB2 expression, providing insights into the upstream molecular interactions of ITGB2. Macrophage infiltration in ESCC is closely associated with ITGB2, which holds significant potential for immunotherapy applications in ESCC. Based on our findings and prior studies, we propose a novel hypothesis: inducing M1 macrophages invitro, knocking out ITGB2, and then reinfusing these ITGB2-knockout M1 macrophages into ESCC patients may represent a promising new immunotherapy strategy, providing a new avenue for ESCC immunotherapy.

Exploration on the Effects and Molecular Mechanisms of Pterostilbene on Esophageal Cancer Based on Network Pharmacology

This study used a network pharmacology approach to analyze the potential role of Pterostilbene (PTS) in esophageal squamous cell carcinoma (ESCC). Compared with traditional ESCC treatments, which often have single targets, limited efficacy, and significant side effects, PTS, as a natural flavonoid compound, offers multiple targets, pathways, strong bioavailability, and blood-brain barrier penetration. These properties may compensate for the shortcomings of conventional drugs. The study constructed the PTS target network and PPI network, systematically analyzing its core targets and related pathways, providing a theoretical foundation for the development of PTS as a new drug for the prevention and treatment of ESCC.

USP8-Dependent Family Tyrosine Kinase Promotes the Malignant Progression of Esophageal Squamous Cell Carcinoma by Upregulating Protein Tyrosine Kinase 2 Expression.

Esophageal squamous cell carcinoma (ESCC) is a lethal malignancy, and the molecular underpinnings of its aggressive behavior are not fully understood. FYN proto-oncogene, Src family tyrosine kinase (FYN) has been linked to cancer progression, yet its role in ESCC remains elusive. This study investigated the influence of FYN on ESCC malignancy. Quantitative real-time polymerase chain reaction was used to assess the mRNA expression of FYN, while western blotting and immunohistochemistry (IHC) assays were performed to detect the protein expression of FYN, ubiquitin specific peptidase 8 (USP8) and protein tyrosine kinase 2 (PTK2). Cell viability was measured with a cell counting kit-8 assay, and cell apoptosis was evaluated using flow cytometry. FYN expression was increased in ESCC tissues and cells when compared with normal esophageal tissues and normal esophageal epithelial cells. Knockdown of FYN inhibited cell invasion, migration, stem-like traits, and glycolysis, while promoting apoptosis. USP8 was shown to stabilize FYN protein expression through its deubiquitinating activity in ESCC cells. Overexpression of FYN reversed the effects of USP8 silencing on the malignant phenotypes of ESCC cells invitro and invivo. FYN upregulated PTK2 expression in both TE1 and KYSE150 cell lines. Furthermore, PTK2 overexpression reversed the effects of FYN silencing on the malignant phenotypes of ESCC cells. Further, USP8 silencing-induced inhibitory effect on PTK2 protein expression was counteracted after FYN overexpression. USP8-dependent FYN contributed to the malignant progression of ESCC by interacting with PTK2. Targeting this pathway may offer a novel therapeutic strategy for ESCC treatment.

Cancer-associated fibroblasts derived-exosomal circ_0076535 promotes esophageal squamous cell carcinoma progression

Background Esophageal cancer (EC) is a common malignant tumor of the digestive tract and an important health-related problem in many developing countries. Esophageal squamous cell carcinoma (ESCC) is the most common subtype of EC. The cancer-associated fibroblasts (CAFs) are the major stromal cells in ESCC microenvironment. They play important role in ESCC proliferation, metastasis, angiogenesis and chemotherapy resistance through paracrine processes. However, the roles of circRNAs enriched in CAF-derived exosmes have not been reported. Objective To explore the mechanisms of how CAF affects ESCC proliferation and metastasis through paracrine processes and to investigate the role of circRNAs enriched in CAF-derived exosomes. Methods Exosomes were isolated from the conditional medium of CAF using differential ultracentrifugation, and then validated by Nanosight analysis. Exosome secretion inhibitor-GW4869 validates the pro-carcinogenic role of exosomes. The qRT-PCR showed the highest expression of circ_0076535 in the exosomal CircRNA, and knockdown of it confirmed its function. Online bioinformatics tool was utilized to predict the potential target gene of circ_0076535, and captured miR-145-5p as the target gene with high predictive value. The targeting association between miR-145-5p and circ_0076535 is further confirmed by the dual luciferase reporter experiment. The stimulation of tumour development and EMT by the CAF-derived exosome circ_0076535 is further validated in vivo. Results In our research, we found that CAF-derived exosomes increased proliferation, migration, invasion and EMT in ESCC cells. Circ_0076535 was highly enriched in CAF-exosomes and transferred into ESCC cells directly depend on internalization of exosomes. CAF-exosomal circ_0076535 increased the level of circ_0076535 in ESCC cells and induced EMT. Mechanistic experiments revealed circ_0076535 acted as a sponge to absorb miR-145-5p and activated NF-κB signaling pathway. Conclusions Conclusively, CAF-exosomal circ_0076535 promoted the ESCC progression via miR-145-5p/NF-κB axis and expected to be a potential biomarker for early diagnosis and treatment of ESCC.

Elaiophylin targets EIF4B to suppress the growth of esophageal squamous cell carcinoma via the PI3K/AKT signaling pathway.

Elaiophylin is known to exert antitumor effects through certain signaling pathways; however, no reports regarding its effects on esophageal cancer are available. This study explored the effects of elaiophylin in esophageal squamous cell carcinoma (ESCC) cells. Transwell and immunofluorescence assays confirmed that elaiophylin inhibited the migration and proliferation of ESCC cells, and western blotting assays showed that it affected apoptosis-related gene expression in ESCC cells. Based on RNA-seq analyses, Single-cell RNA-seq, a human cancer pathway phosphorylation antibody array, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomics analyses, we found that elaiophylin was related to low expression of EIF4B and activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. In both in vitro and in vivo experiments, ESCC cells treated with elaiophylin showed low EIF4B expression, which inhibited their proliferation and promoted apoptosis by activating the PI3K/AKT signaling pathway; EIF4B overexpression could reverse these effects of elaiophylin on ESCC cells. Therefore, our results indicate that elaiophylin targets EIF4B to inhibit ESCC cell proliferation via the PI3K/AKT signaling pathway. Targeting elaiophylin or the EIF4B/PI3K/AKT signaling pathway may produce new methods for ESCC treatment.

Ivermectin inhibits the growth of ESCC by activating the ATF4-mediated endoplasmic reticulum stress-autophagy pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common forms of malignancy worldwide. However, there is currently a lack of effective chemotherapeutic drugs for ESCC. Ivermectin is a broad-spectrum antiparasitic drug with notable antitumor activity. However, the cellular and molecular mechanisms by which ivermectin inhibits cancer growth remain unclear. In this study, we elucidate the role of ivermectin in ESCC suppression by activating the endoplasmic reticulum (ER) stress and autophagy pathways. In transcriptome analyses, we find that activating transcription factor 4 (ATF4) and DNA damage inducible transcript 3 (DDIT3) are involved in the activation of ER stress by ivermectin. Moreover, ivermectin treatment suppresses the growth of ESCC xenograft tumors in nude mice. Taken together, our results establish the antitumor molecular role of ivermectin in targeting the ER stress-autophagy pathway and suggest that ivermectin is a potential drug candidate for the treatment of ESCC.

Co-targeting TMEM16A with a novel monoclonal antibody and EGFR with Cetuximab inhibits the growth and metastasis of esophageal squamous cell carcinoma.

The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC.

Neoadjuvant Chemotherapy vs Chemoradiotherapy for Malignancy of Esophagus: A Prospective Comparative Study.

Neoadjuvant chemoradiation (NACRT) followed by surgery has become the standard of care for esophageal squamous cell carcinoma (ESCC). This study compared the tolerability and oncological benefit of neoadjuvant chemotherapy (NACT) with those of NACRT for the treatment of ESCC. A prospective quasi-experimental comparative study was conducted from July 2019 to August 2023 to assess the efficacy of the NACT regimen of two cycles of paclitaxel and carboplatin as an alternative to standard NACRT. Either NACT or NACRT was given to patients with resectable ESCC (clinical stage IB-IIIC), after which they underwent minimally invasive esophagectomy with two-field lymphadenectomy. Radiological and pathological responses to neoadjuvant therapy, perioperative morbidity, mortality, and recurrence-free and overall survival rates were compared. Out of the 74 patients enrolled, 63 were included in the study after exclusion. Of these, 30 received NACT, and 33 received NACRT. The baseline demographics, tumor characteristics, incidence of neoadjuvant therapy-related adverse events, and perioperative morbidity were comparable between the two groups. The median number of lymph nodes retrieved (21 vs 19, p=0.19) and R0 resection rate (100% vs 94%) were similar. Although the pathological response was significantly better in the NACRT arm, at a median follow-up of 32.5 (20.75-48) months, there was a non-significant trend toward better recurrence-free survival in the NACRT group (57 vs 36 months, p-value - 0.831), with median overall survival yet to be achieved in both groups. Compared with NACRT, NACT for ESCC is well tolerated and has non-inferior oncological outcomes. NACT could be a feasible alternative to NACRT in such patients, especially if the radiotherapy option is not feasible or available.

ΔNp63α promotes radioresistance in esophageal squamous cell carcinoma through the PLEC-KEAP1-NRF2 feedback loop.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly prevalent in China, exhibiting resistance to current treatments. ΔNP63α, the main isoform of p63, is frequently amplified in ESCC and contributes to therapeutic resistance, although the molecular mechanisms remain unknown. Here, we report that ΔNP63α is highly expressed in ESCC and is associated with radioresistance by reducing ROS level. Furthermore, ΔNP63α plays a critical role in radioresistance by directly transactivating the expression of PLEC. PLEC competitively interacts with KEAP1, resulting in the release of NRF2 from KEAP1 and its translocation from the cytosol to the nucleus, where it activates gene expression to facilitate ROS elimination. Additionally, radiotherapy-induced ROS also activates ΔNP63α expression via NRF2. Pharmacologic inhibition of NRF2 effectively improves radiosensitivity in nude mice. Collectively, our results strongly suggest that the ΔNp63α/PLEC/NRF2 axis plays a key role in radioresistance in ESCC, indicating that targeting NRF2 is a promising therapeutic approach for ESCC treatment.

Clinical efficacy of Endostar continuous infusion combined with concurrent chemoradiotherapy in the treatment of oesophageal squamous cell carcinoma.

To evaluate the effectiveness and safety of concurrent chemoradiotherapy using Endostar continuous infusion for treating oesophageal squamous cell carcinoma (OSCC). A total of 62 patients with oesophageal carcinoma were divided into three groups: the Endostar continuous infusion group (n = 27), the Endostar intravenous drip group (n = 21) and the concurrent chemoradiotherapy group (n = 14). All patients underwent oesophageal radiotherapy (56-60 Gy) alongside concurrent chemotherapy (4 mg of raltitrexed +100 mg of oxaliplatin, two cycles). In the Endostar continuous infusion group, 210 mg of Endostar was administered via infusion once every 3 weeks for 72 h, repeated for two cycles. The Endostar intravenous drip group received a dosage of 15 mg/day of Endostar, administered once daily for 14 days, repeated for two cycles. The objective response rate (ORR) (complete remission + partial remission), progression-free survival (PFS), 2-year overall survival (2y-OS) and adverse reactions were observed. In the Endostar continuous infusion, intravenous drip and concurrent chemoradiotherapy groups, the ORR was 100, 95.2 and 78.6%, respectively (p < 0.05). There was a statistically significant difference between the continuous infusion and concurrent chemoradiotherapy groups (p < 0.05). However, there was no statistically significant difference between the continuous infusion and intravenous drip groups or the intravenous drip and concurrent chemoradiotherapy groups (p > 0.05). The continuous infusion and intravenous drip groups had higher PFS rates than the concurrent chemoradiotherapy group (p < 0.05). Regarding the 2y-OS rate, no statistically significant difference was observed among the three groups (p > 0.05). Furthermore, there was no statistically significant difference in adverse reactions among the groups (p > 0.05). Concurrent chemotherapy based on endostatin is effective and safe in the treatment of OSCC. Continuous 3-day Endostar infusion treatment can significantly enhance both short-and long-term therapy efficacy in patients while maintaining a high level of safety.

Comparative Analysis of Concurrent Chemoradiotherapy Versus Chemotherapy Alone as First-Line Palliative Treatments for Advanced Esophageal Squamous Cell Carcinoma.

Background: In advanced-stage esophageal squamous cell carcinoma (ESCC), treatment of both the primary tumor and metastatic sites is imperatively required. Consequently, an optimal treatment modality should effectively control both aspects. Therefore, the benefits of concurrent chemoradiotherapy (CCRT) in cases of advanced-stage ESCC should be evaluated. Methods: This retrospective study compared the efficacy and safety of CCRT versus chemotherapy alone for advanced-stage ESCC patients from January 2012 to December 2023 at a university hospital in Southern Thailand. Survival was assessed using the Kaplan-Meier approach, with comparisons being made by the log-rank test. A p-value of <0.05 indicated statistical significance. Results: From a total of 196 patients with stage IV ESCC, 117 (59.7%) received CCRT, while 79 (40.3%) received chemotherapy alone. The median overall survival (OS) time was 9.04 months for CCRT and 5.79 months for chemotherapy (hazard ratio, HR: 0.58 [0.43-0.78]). CCRT significantly improved OS time in stage IVA patients (HR: 0.52 [0.29-0.93]), but not in stage IVB patients (HR: 0.76 [0.51-1.11]). The median progression-free survival (PFS) time was 6.04 months for CCRT and 3.50 months for chemotherapy (HR 0.48 [0.35-0.65]). The objective response rates (ORRs) were 43.6% and 22.8%, respectively (p = 0.003). Hematological toxicities were more common with CCRT, along with mild cases of treatment-associated pneumonitis and dermatitis. Conclusions: Although palliative chemotherapy is the standard treatment for advanced-stage ESCC, CCRT provides significant benefits for patients with stage IVA ESCC, improving OS, PFS, and ORRs, despite there being a higher incidence of adverse events. Thus, CCRT should be considered for patients with stage IVA ESCC with a good performance status.

TMSB4Y restrains sphingomyelin synthesis via de novo purine synthesis to exert a tumor suppressor function in male esophageal squamous cell carcinoma.

Y chromosome genes play a vital role in sex difference of cancer. The dysregulation and functional implications of Y chromosome genes in esophageal squamous cell carcinoma (ESCC) remains elusive. Here, we analyze the Y chromosome gene signature and identify TMSB4Y as an emerging prognostic predictor in male ESCC. Functional analyses show that TMSB4Y inhibits the proliferation, invasion and metastasis of male ESCC cells. Mechanistically, we demonstrate that TMSB4Y interacts with PAICS, wherein TMSB4Y disrupts the formation of the PAICS octamer to inhibit purine de novo synthesis, leading to a decrease in the AMP/ATP ratio, subsequently impeding AMPK phosphorylation. Furthermore, we uncover a regulatory cascade orchestrated by the TMSB4Y/PAICS-AMPK axis, which exerts a suppressive effect on sphingomyelin metabolism by inhibiting the expression of sphingomyelin synthases (SMSs). Notably, Malabaricone C, an inhibitor of SMS1 and SMS2, effectively suppresses male ESCC cell proliferation and xenograft tumor growth. Collectively, these findings reveal the regulation of sphingomyelin metabolism by TMSB4Y/PAICS-AMPK axis and underscore the potential of targeting SMSs as a promising therapeutic approach for the treatment of male ESCC.

Artificial intelligence enhances the management of esophageal squamous cell carcinoma in the precision oncology era

Esophageal squamous cell carcinoma (ESCC) is the most common histological type of esophageal cancer with a poor prognosis. Early diagnosis and prognosis assessment are crucial for improving the survival rate of ESCC patients. With the advancement of artificial intelligence (AI) technology and the proliferation of medical digital information, AI has demonstrated promising sensitivity and accuracy in assisting precise detection, treatment decision-making, and prognosis assessment of ESCC. It has become a unique opportunity to enhance comprehensive clinical management of ESCC in the era of precision oncology. This review examines how AI is applied to the diagnosis, treatment, and prognosis assessment of ESCC in the era of precision oncology, and analyzes the challenges and potential opportunities that AI faces in clinical translation. Through insights into future prospects, it is hoped that this review will contribute to the real-world application of AI in future clinical settings, ultimately alleviating the disease burden caused by ESCC.