Esophageal Squamous Cell Carcinoma Therapy Research Articles

Envafolimab plus chemotherapy as neoadjuvant therapy for resectable esophageal squamous cell carcinoma (ESCC): A prospective, single-arm, phase II study.

e14633 Background: Currently, chemotherapy plus PD-1 inhibitor immunotherapy has become a promising option in the neoadjuvant setting of resectable ESCC, nevertheless, the PD-ligand 1 (PD-L1) blockade-based combination has rarely been investigated to date. Envafolimab is the first and only globally approved subcutaneous (SC) PD-L1 inhibitor, which has shown satisfactory efficacy and safety profile in tumors. This Simon’s two-stage, phase II study explored the safety and feasibility of SC administration of envafolimab as an alternative to intravenous (IV) administration of PD-1/PD-L1 inhibitors in the neoadjuvant therapy of resectable ESCC. Here, we reported the results of the stage 1. Methods: In this Simon’s two-stage, phase II study, patients initially treated with locally advanced and resectable (stage II-IVA) ESCC were enrolled and received envafolimab (300mg, SC, day 1), albumin-bound paclitaxel (130mg/m2, IV, days 1 and 8), and carboplatin (AUC = 5, day 1) every 3 weeks for 3 cycles. The primary endpoints were safety and pathological complete response (pCR). A Simon’s two-stage design was utilized with following assumptions. Target accrual was 13 patients in the first stage (If 3 or more patients had pCR in stage 1, study could continue in stage 2), total 34 patients were enrolled in the stage 2. Secondary endpoints were major pathological response (MPR). Safety was assessed by adverse events (AEs) and postoperative complications. Results: Between October 2022 and April 2023, 13 (81.3%) of 16 enrolled patients completed neoadjuvant therapy and underwent surgery. All 13 (100%) surgical patients underwent successful R0 resection; of whom, 8 (61.5%) achieved pCR and 9 (69.2%) achieved MPR, respectively. Downstaging occurred in 10 (76.9%) of 13 patients. pCR and MPR were identified to be associated with tumor downstaging but not with PD-L1 expression. CPS levels in MPR and pCR group were significantly higher than that in Non- MPR and Non-pCR group. Grade 3-4 treatment-related AEs (TRAEs) and immune-related AEs (IrAEs) occurred in 12.5% and 37.5% of 16 patients, respectively. 10 (76.9%) of 13 patients reported postoperative complications. No treatment-related surgical delay or death occurred. Conclusions: Envafolimab plus chemotherapy as neoadjuvant therapy demonstrated promising antitumor activity for resectable ESCC with high rates of pCR, MPR and R0 resection, as well as acceptable tolerability. Based on the encouraging efficacy of our regimen in the first stage, we will continue the enrollment of patients in stage 2. Keywords: Esophageal squamous cell carcinoma; Envafolimab; Neoadjuvant therapy; Chemotherapy Clinical trial information: NCT05552651 .

Update results of anlotinib combined with TQB2450 (PD-L1 blockade) as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, multicenter, open-label phase II clinical trial.

e16035 Background: Recent studies have demonstrated encouraging efficacy in patients with ESCC when combining PD-1 blockades with chemotherapy in the first-line setting. However, the safety profile of conventional chemotherapy remains unsatisfactory, suggesting the chemotherapy-free regimen a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, has shown therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China. TQB2450 is a novel PD-L1 blockade developed by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (Nanjing, China). This study aims to investigate the efficacy and safety of anlotinib plus TQB2450 as first-line therapy for patients with advanced ESCC. Preliminary results were presented at the 2023 ASCO-GI Symposium (Abs 377), the 2023 ASCO (Abs 4041) and the 2023 ESMO (1531P), the consecutively updated results were presented in this report. Methods: Patients with previously untreated metastatic or locally advanced ESCC, whose age was between 18 and 75 years, with ECOG PS of 0 or 1 score and life expectancy of > 3 months were inclusion criteria. Eligible patients were administered with anlotinib (12mg, po, d1~14, q3w) plus TQB2450 (1200mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 and iRECIST using CT scans every 2 cycles for the first 6 cycles, and every 3 cycles thereafter. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 46. The primary endpoint was ORR, secondary endpoints included safety, PFS, DCR, DoR and OS. Results: From Mar 2022 to Sep 2022, a total of 46 patients were enrolled. At the data cut-off date (Dec, 2023), there were 1 CR (2.2%), 31 PR (67.4%), 10 SD (21.7%), 1 PD (2.2%) and 3 NE (6.5%). Therefore, the preliminary ORR was 69.6% (95%CI: 54.2%~82.3%), DCR was 91.3% (95%CI: 79.2%~97.6%). At the data cut-off date, 16 patients discontinued treatment due to PD, the preliminary prognostic result exhibited that the median PFS of the 46 pts was 15.44 months (95%CI: NA~NA). Additionally, safety profile exhibited that the regimen was tolerable. The common grade ≥3 treatment-related adverse events in 46 patients were hypertension (8.7%), neutrophil count decreased (4.3%), hyponatremia (4.3%), lymphocyte count decreased (4.3%), white blood cell count decreased (2.2%), platelet count decreased (2.2%), hand-foot syndrome (2.2%), hemoptysis (2.2%) and toothache (2.2%). Conclusions: The preliminary results highlighted that anlotinib plus TQB2450 as a first-line therapy for advanced ESCC showed encouraging efficacy and manageable safety profile. Furthermore, these conclusions required to be confirmed in subsequent trials. Clinical trial information: NCT05038813 .

Update results of anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

e16017 Background: Recently, PD-1 blockades combined with dual chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might be a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for patients with ESCC in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Preliminary results were presented at the 2024 ASCO-GI Symposium (Abs 340), the consecutively updated results were presented in this report. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m2, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Dec 2023, a total of 27 patients were enrolled, 25 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (4.0%), 18 PR (72.0%), 3 SD (12.0%) and 3 NE (12.0%). Therefore, the preliminary ORR was 76.0% (95%CI: 54.9%-90.6%), DCR was 88.0% (95%CI: 68.8%-97.5%). Median PFS of the 25 patients was not yet reached. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 27 patients with the incidence > 20% were anemia (40.7%), peripheral nerve toxicity (37.0) and white blood cell decreased (25.9%). Common grade ≥3 treatment-emergent adverse events were white blood cell decreased (7.4%), diarrhea (3.7%), glutamic-pyruvic transaminase was elevated (3.7%), glutamic oxalacetic transaminase increased (3.7%), hypertension (3.7%) and immune enteritis (3.7%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials.

Agaricus blazei murrill and Enteromorpha prolifera-derived polysaccharides gain therapeutic effects on esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC), the most common pathological type of esophageal cancer, is one of the leading causes of cancer death worldwide, but an effective therapeutic avenue is still absent. This study was to evaluate the therapeutic effect of Agaricus blazei Murrill polysaccharides (ABP) and Enteromorpha prolifera polysaccharides (EP) on ESCC. The results showed that both ABP and EP have therapeutic effects on multiple malignant processes of ESCC, such as proliferation, migration, invasion, and apoptosis, in vitro. Moreover, both ABP and EP retard tumor growth in vivo and the growth of ESCC-derived organoids. A series of genes and proteins changed upon treatments with ABP and EP after RNA sequencing and proteomics analysis. Autophagy, mitophagy and ferroptosis were enriched after treatments with these two polysaccharides, suggesting that the consumption of ABP and EP may represent a promising dietary supplement for ESCC therapy.

HLA-A+ tertiary lymphoid structures with reactivated tumor infiltrating lymphocytes are associated with a positive immunotherapy response in esophageal squamous cell carcinoma.

Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance. We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients. Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A+ TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A+ cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. HLA-A+ TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.

Development of a Specific Aptamer-Modified Nano-System to Treat Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a prevalent gastrointestinal cancer characterized by high mortality and an unfavorable prognosis. While combination therapies involving surgery, chemotherapy, and radiation therapy are advancing, targeted therapy for ESCC remains underdeveloped. As a result, the overall five-year survival rate for ESCC is still below 20%. Herein, ESCC-specific DNA aptamers and an innovative aptamer-modified nano-system is introduced for targeted drug and gene delivery to effectively inhibit ESCC. The EA1 ssDNA aptamer, which binds robustly to ESCC cells with high specificity and affinity, is identified using cell-based systematic evolution of ligands by exponential enrichment (cell-SELEX). An EA1-modified nano-system is developed using a natural egg yolk lipid nanovector (EA1-EYLNs-PTX/siEFNA1) that concurrently loads paclitaxel (PTX) and a small interfering RNA of Ephrin A1 (EFNA1). This combination counters ESCC's proliferation, migration, invasion, and lung metastasis. Notably, EFNA1 is overexpressed in ESCC tumors with lung metastasis and has an inverse correlation with ESCC patient prognosis. The EA1-EYLNs-PTX/siEFNA1 nano-system offers effective drug delivery and tumor targeting, resulting in significantly improved therapeutic efficacy against ESCC tumors. These insights suggest that aptamer-modified nano-systems can deliver drugs and genes with superior tumor-targeting, potentially revolutionizing targeted therapy in ESCC.

Development of an Interpretable Deep Learning Model for Pathological Tumor Response Assessment After Neoadjuvant Therapy.

Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption(Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhancethe efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Integrating bulk and single-cell sequencing data to construct a Scissor+ dendritic cells prognostic model for predicting prognosis and immune responses in ESCC

Esophageal squamous cell carcinoma (ESCC) is characterized by molecular heterogeneity with various immune cell infiltration patterns, which have been associated with therapeutic sensitivity and resistance. In particular, dendritic cells (DCs) are recently discovered to be associated with prognosis and survival in cancer. However, how DCs differ among ESCC patients has not been fully comprehended. Recently, the advance of single-cell RNA sequencing (scRNA-seq) enables us to profile the cell types, states, and lineages in the heterogeneous ESCC tissues. Here, we dissect the ESCC tumor microenvironment at high resolution by integrating 192,078 single cells from 60 patients, including 4379 DCs. We then used Scissor, a method that identifies cell subpopulations from single-cell data that are associated bulk samples with genomic and clinical information, to stratify DCs into Scissorhi and Scissorlow subtypes. We applied the Scissorhi gene signature to stratify ESCC scRNAseq patient, and we found that PD-L1, TIGIT, PVR and IL6 ligand-receptor-mediated cell interactions existed mainly in Scissorhi patients. Finally, based on the Scissor results, we successfully developed a validated prognostic risk model for ESCC and further validated the reliability of the risk prediction model by recruiting 40 ESCC clinical patients. This information highlights the importance of these genes in assessing patient prognosis and may help in the development of targeted or personalized therapies for ESCC.

En1 promotes cell proliferation and migration via Hedgehog signaling pathway in esophageal squamous cell carcinoma

Objective: To explore the function and mechanism of transcription factor En1 in esophageal squamous cell carcinoma (ESCC). Methods: The correlations of En1 with prognosis were analyzed using the overall survival data of 9 397 pan-cancer patients and progression-free survival data of 4 349 pan-cancer patients from The Cancer Genome Atlas (TCGA) database. The En1 expression data in 53 and 155 cases of ESCC and their paired adjacent tissues were from Gene Expression Omnibus (GEO) database and National Genomics Data Center-Genome Sequence Archive(NGDC-GSA)database. Lentivirus was used to generate En1 stable knockout cell lines KYSE180 and KYSE450. The proliferation ability of the cells was detected by cell counting kit 8 and clone formation assay. The migration ability of the cells was detected by Transwell assay. The effect of En1 on the proliferation of ESCC was detected by xenograft experiment in BALB/c-nu/nu mice. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of En1, glioma-associated oncogene family zinc finger 1 (GLI1), glioma-associated oncogene family zinc finger 2 (GLI2) and smoothened (SMO). Results: Pan-cancer data from TCGA showed that patients with low En1 expression had longer overall survival and progression-free survival than patients with high En1 expression (P< 0.001). Data from GEO and GSA databases also showed a high expression level of En1 in ESCC tissues compared with paired tissues (P＜0.001). Proliferation was inhibited after knockout of En1 in KYSE180 and KYSE450 cells (P＜0.001). The colony formation numbers decreased. The colony formation numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 138.33±23.07 and 127.00±19.70, respectively, significantly lower than that of the shNC group 340.67±12.06 (P<0.001). The colony formation numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 65.33±2.52 and 9.00±3.00, respectively, significantly lower than that of the shNC group 139.00±13.00 (P<0.001). The migration numbers was inhibited after knockout of En1 [the Transwell numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 66.67±12.66 and 71.33±11.02, respectively, significantly lower than that of the shNC group 334.67±16.56 (P<0.001). The Transwell numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 112.33±14.57 and 54.33±5.51, respectively, significantly lower than that of the shNC group 253.33±21.03 (P<0.001)]. Xenograft model showed a slower growth rate of shEn1#1 and shEn1#2 cell lines (P＜0.001). The tumor weights of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were (0.046±0.026)g and (0.047±0.025)g, respectively, significantly lower than that of the shNC group (0.130±0.038)g (P＜0.001). After knockdown of En1, the relative expression levels of GLI1 in KYSE180 cells of the shEn1#1 group and the shEn1#2 group were 0.326±0.162 and 0.322±0.133, and the relative expression levels of GLI1 in KYSE450 cells of the shEn1#1 and shEn1#2 groups were 0.131±0.006 and 0.352±0.050, respectively, which were all lower than that in the shNC group (P＜0.01). After knockdown of En1, overexpression of GLI1 attenuated the inhibitory effect of knockdown of En1 on cell proliferation (P＜0.001), colony formation[the colony formation numbers of the shEn1#1-GLI1 group were 151.00±9.54, higher than 102.33±10.02 (P=0.004) of the shEn1#1-vector group] and migration [the migration numbers of the shEn1#1-GLI1 group were 193.67±10.07, higher than 109.33±11.50 (P<0.001) in the shEn1#1-vector group]. In clinical samples of ESCC, major regulatory factors of the Hedgehog pathway were up-regulated and the pathway was activated. Conclusion: En1 promotes the proliferation and migration of ESCC cells by regulating the Hedgehog pathway and can be used as a new potential target for targeted therapy of ESCC.

Artesunate-loaded solid lipid nanoparticles resist esophageal squamous cell carcinoma by inducing Ferroptosis through inhibiting the AKT/mTOR signaling

Esophageal squamous cell carcinoma (ESCC) is a severe malignancy with high incidence and mortality rate in China, while the application of standard chemotherapeutic drugs for ESCC meets the barriers of high toxicity and multiple drug resistance (MDR). In recent years, the anticancer effects of artesunate (ART), a Chinese medicine monomer have gained extensive attentions due to its characteristics of low toxicity, high potency, and reversal of MDR. In this study, we develop the artesunate-loaded solid lipid nanoparticles (SLNART) to overcome the poor water solubility and bioavailability of ART, further improving the efficiency of ART on ESCC treatment. Especially mentioned, SLNART is shown to present marked inhibitory effects on ESCC development based on the induction of ferroptosis by two pathways included upregulating TFR to increase Fe2+ ions and inhibiting the AKT/mTOR signaling to downregulate GPX4. Collectively, this study is the first to pave a promising approach for ESCC therapy based on a strategy of developing SLNART to induce ferroptosis by mediating Fe2+ ions and AKT/mTOR signaling.

The efficacy and safety of conversion therapy after initial systemic chemotherapy in advanced esophageal cancer with distant metastases: A multicenter retrospective observational study.

310 Background: Systemic chemotherapy, with or without radiation, has been the standard treatment for esophageal squamous cell carcinoma (ESCC) with distant metastasis. The increased efficacy of multimodality treatment allows for the consideration of conversion therapy with curative intent for initially unresectable ESCC after initial treatment. In the present study, we examined the safety and effectiveness of conversion therapy for ESCC. Methods: Conversion therapy was defined as surgery or chemoradiation therapy (CRT) aiming at cure after initial treatment for tumors that were initially unresectable due to distant metastasis. The patients who underwent conversion therapy for ESCC between 2011 and 2021 at participating institutions were retrospectively reviewed. Patient backgrounds, treatment outcomes, and overall survival (OS) were evaluated. Results: From 22 institutions, 149 patients were enrolled. As defined, all patients received systemic chemotherapy as an initial treatment. The distant metastatic sites in para-aortic lymph nodes/extra regional mediastinal lymph nodes/lung/liver/bone/others were 81(54%)/19 (13%)/14 (9%)/11 (7%)/4 (3%)/20 (14%), respectively. After the initial treatment, 116 patients underwent surgery and 33 patients received CRT as conversion therapy. Of 116 patients who underwent conversion surgery, the incidence rate of postoperative pneumonia/leakage/recurrent laryngeal nerve palsy was 16%/7%/6%, respectively. R0 resection was obtained in 87%. Regarding the non-hematological toxicities during conversion CRT (CTCAE grade 3 or higher), decreased appetite/dysphagia/esophagitis was 21%/15%/9%, respectively. No grade 4 or higher hematologic toxicities were observed. The 3-year OS (3y-OS) rate for all patients was 41.9%; no significant differences were found between surgery and CRT groups (43.3% vs 37.0%, p = 0.112). Pathological responders showed a significantly longer OS than non-responders (3y-OS, 56.4% vs 36.1%, p = 0.010). The distribution or number of distant metastases were not identified as prognostic factors. Conclusions: This study showed that conversion therapy for ESCC patients with distant metastasis could be conducted safely and have a favorable prognosis. Since its survival benefit would depend on the pathological response, it is important to develop an indicator to predict pathological response before surgery and carefully select appropriate candidates of conversion therapy in ESCC.

Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

340 Background: Recently, PD-1 blockades combined with dual chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might be a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for patients with ESCC in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m2, iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Aug 2023, a total of 23 patients were enrolled, 19 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 14 PR (73.7%), 2 SD (10.5%) and 3 NE (15.8%). Therefore, the preliminary ORR was 73.7% (95%CI: 48.8%-90.9%), DCR was 84.2% (95%CI: 60.4%-96.6%). Median PFS of the 19 patients was not yet reached. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 23 patients with the incidence &gt;20% were leukopenia (30%) and anemia (30%). Common grade ≥3 treatment-emergent adverse events were leukopenia (9%), glutamic-pyruvic transaminase was elevated (4%), glutamic oxaloacetic transaminase increased (4%), hypertension (4%) and diarrhea (4%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. The conclusions needed to be confirmed in subsequent trials.

Prognostic role of pathologic status other than complete response after neoadjuvant therapy followed by surgery in esophageal squamous cell carcinoma.

This retrospective study was performed to investigate the survival differences according to the pathologic status after neoadjuvant chemotherapy followed by surgery in esophageal squamous cell carcinoma (ESCC), and to investigate whether current AJCC 8th ypStage can predict survival accurately. Data of 563 patients who received neoadjuvant therapy and esophagectomy for ESCC between 1994 and 2018 were retrospectively reviewed. The mean age was 62.00 ± 8.01years, of which 524 (93.1%) were males. The median follow-up period was 29.12months. A total of 153 (27.1%) patients showed pathologic complete response (pCR) and 92 (16.3%) patients showed pCR of the primary lesion with residual metastatic lymph nodes (ypT0N +). A total of 196 (35%) and 122 (21.6%) patients showed ypT + N + and ypT + N, respectively. The 5-year overall survival (OS) of each group was 75.1% (CR), 42.4% (ypT + N0), 54.9% (ypT0N +), and 26.1% (ypT + N +); CR patients showed better survival than the other groups, and no survival differences were found in the 5-year OS between ypT + N0 and ypT0N + patients (p = 0.811). In ypStage I, there were survival differences between ypT0N0 and ypTis-2N0 patients, and ypT1N0 (ypStage I) and ypT0N1 (ypStageIIIA) showed similar OS (5-year OS in 49.3% vs. 67.1%, p = 0.623). pCR offers long-term survival in patients; however, survival significantly declines with the presence of residual primary lesion and nodal metastases.

Efficacy and toxicity of anlotinib plus camrelizumab versus anlotinib plus S-1 as second-line therapy for advanced esophageal squamous cell carcinoma: A real-world retrospective study

BackgroundNo data exist on the efficacy and safety of anlotinib plus camrelizumab doublet as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC). Although anlotinib and the programmed death-1 (PD-1) inhibitor camrelizumab are used as treatments for ESCC, the combined use of anlotinib and camrelizumab as a second-line therapy has not been reported. Therefore, this study explored the efficacy and toxicity of anlotinib plus camrelizumab as second-line therapy for advanced ESCC. MethodsFifty-eight patients with advanced ESCC undergoing second-line therapy, either with anlotinib plus camrelizumab or anlotinib plus S-1, were enrolled and retrospectively analyzed at Jiangsu Province Hospital of Chinese Medicine from January 2020 to December 2021. The primary endpoint was progression-free survival (PFS), with secondary endpoints including the objective response rate (ORR), disease control rate (DCR), and assessment of toxicity. ResultsIn patients with advanced ESCC, the anlotinib plus camrelizumab group exhibited longer PFS (8.00 vs. 4.53 months, P < 0.001), higher ORR ( 28.1 vs. 19.2%, P = 0.431), and higher DCR (87.5 vs. 65.4%, P = 0.045) than in the anlotinib plus S-1 group. Treatment-related adverse events (TRAEs) were predominantly grade 1/2 in both groups, with a higher incidence of grade 1/2 skin toxicity in patients treated with anlotinib plus camrelizumab (P = 0.034). Two patients (6.3%) developed grade 1/2 immune-related pneumonia. The incidence of grade 3/4 TRAEs did not differ significantly between the two groups. Multivariable Cox regression analysis identified that the drug regimen (P < 0.001), Eastern Cooperative Oncology Group performance status (P = 0.008), and differentiation grade (P = 0.008) were independent prognostic factors for PFS. ConclusionsAnlotinib plus camrelizumab exhibited promising antitumor efficacy and manageable toxicity when used as a second-line treatment for advanced ESCC.

TAPI-1 Exhibits Anti-tumor Efficacy in Human Esophageal Squamous Cell Carcinoma Cells via Suppression of NF-κB Signaling Pathway

BackgroundTNF-α processing inhibitor-1 (TAPI-1) is a known metalloproteinase inhibitor with potential anti-inflammatory effects. However, its anti-cancer effects on esophageal squamous cell carcinoma (ESCC) have not been uncovered.AimIn the present study, the effects of TAPI-1 on ESCC cell viability, migration, invasion, and cisplatin resistance and the underlying molecular mechanisms were investigated in TE-1 and Eca109 cells.MethodsTo this end, TE-1 and Eca109 cells were exposed to TAPI-1 for indicated time intervals. Cell viability was assessed using cell counting kit-8 assay and apoptosis was evaluated using flow cytometry assay. Migration and invasion were assessed using Transwell assays. Gene expressions were analyzed using quantitative reverse transcription polymerase chain reaction. The activation of NF-κB signaling pathway was elucidated via Western blot and chromatin immunoprecipitation assay.ResultsWe observed that higher doses (10, 20 μM) of TAPI-1 inhibited ESCC cell viability, while a lower dose (5 μM) of TAPI-1 inhibited ESCC cell migration and invasion and enhanced the chemosensitivity of ESCC cells to cisplatin. Moreover, TAPI-1 suppressed the activation of NF-κB signaling and the target genes expression in the stage of transcription initiation. Furthermore, blocking NF-κB signaling in advance could abolish all the effects of TAPI-1 on ESCC cells.ConclusionOverall, these results indicated that TAPI-1 impairs ESCC cell viability, migration, and invasion and facilitates cisplatin-induced apoptosis via suppression of NF-κB signaling pathway. TAPI-1 may serve as a potential adjuvant agent with cisplatin for ESCC therapy.

Modern approaches to esophageal squamous cell carcinoma therapy: paradigm shift?

Esophageal cancer (EC) is one of the most aggressive malignant neoplasms, ranking sixth among oncological causes of death. According to GLOBOCAN, more than half a million people die from this disease every year, and by 2040 this indicator is expected to increase almost twice. In most patients, esophageal cancer is diagnosed at stages III–IV of the disease. Currently, the standard of treatment for inoperable patients with EC is simultaneous chemoradiotherapy.One of the main methods of treatment of patients with non-metastatic esophageal lesion remains surgical intervention in the volume of esophagectomy with radical lymph dissection, accompanied by quite frequent serious postoperative complications. However, the results of surgical treatment of locally advanced esophageal cancer alone remain unsatisfactory, and the fiveyear survival rate is less than 20 %. In order to improve the oncological results of treatment, various combinations of drug and radiation therapy are used (preoperative chemotherapy or chemoradiotherapy, independent chemoradiotherapy). To date, recommendations for the treatment of locally advanced esophageal cancer vary from country to country. Trimodal therapy (preoperative chemoradiotherapy up to TFD – 46 Gy with 5 cycles of weekly chemotherapy according to the carboplatin + paclitaxel scheme followed by surgical treatment) is the standard in operable patients with non-metastatic squamous cell carcinoma of the esophagus in our and European countries. In Asian countries, preference is given to neoadjuvant chemotherapy, based on the data of the JCOG1109 (NExT) study, in which it was shown that the addition of docetaxel to neoadjuvant therapy with cisplatin and fluorouracil is accompanied by an improvement in overall survival and acceptable toxicity, compared with the CF regimen and chemoradiotherapy. A separate issue is the place of lifesaving esophagectomy in patients who have received a course of radical chemoradiotherapy. Unfortunately, according to several researchers, recurrent or persistent esophageal cancer remains an urgent problem with a risk of relapse of the disease in up to 60 % of cases.We have studied the data of the Russian and global literature concerning the treatment of squamous cell carcinoma of the esophagus.

The m6A reader IGF2BP2 promotes the progression of esophageal squamous cell carcinoma cells by increasing the stability of OCT4 mRNA.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy with high morbidity and mortality. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) serves as a reader of RNA m6A (N6 methyladenosine) modification to regulate gene expression at the post-transcriptional level. Emerging evidence suggests that IGF2BP2 plays critical roles in tumorigenesis and malignant development. However, the biological function and molecular mechanism of IGF2BP2 in ESCC are not well understood. Here, we found that IGF2BP2 expression was upregulated in esophageal cancer tissues and ESCC cells, and IGF2BP2 overexpression enhanced proliferation, migration, invasion, and stem cell-like properties of ESCC cells. Conversely, the knockdown of IGF2BP2 expression inhibited malignant phenotype of ESCC cells. Mechanistically, IGF2BP2 upregulated octomer-binding transcription factor 4 (OCT4) mRNA expression, and RNA immunoprecipitation (RIP) assay proved that IGF2BP2 could interact with OCT4 mRNA. Moreover, OCT4 was modified at m6A confirmed by methylated m6A RNA immunoprecipitation (Me-RIP)-qPCR assay, and IGF2BP2 knockdown reduced OCT4 mRNA stability. These results suggested that IGF2BP2 served as a reader for m6A-modified OCT4, thus increased OCT4 mRNA expression by regulating its stability. Furthermore, the knockdown of OCT4 could reverse the effects of IGF2BP2 on ESCC cells. In conclusion, these data indicate that IGF2BP2, as a reader for m6A, plays an oncogenic role by regulating OCT4 expression in ESCC, which provides new insights into targeting IGF2BP2/OCT4 axis for the therapy of ESCC.

Skeletal Muscle Quality and Quantity Affect Prognosis after Neoadjuvant Chemotherapy with a Triple Regimen of Docetaxel/Cisplatin/5-FU in Patients with Esophageal Cancer

The purpose of this study was to identify factors associated with the prognosis after docetaxel, cisplatin, and 5-fluorouracil (DCF) neoadjuvant chemotherapy (NAC) in patients with advanced esophageal squamous cell carcinoma (ESCC) undergoing surgical resection. We retrospectively examined a total of 100 patients who received neoadjuvant DCF therapy for ESCC at our institution between 2011 and 2020. The psoas muscle index (PMI) was calculated from the psoas muscle area at the L3 vertebral level, and the intramuscular adipose tissue content (IMAC) was calculated from the mean CT value of the multifidus muscle and from four points of subcutaneous fat. The median PMI value was 6.11 cm2/m2 (range, 3.12–11.07 cm2/m2) in men and 3.65 cm2/m2 (range, 2.70–6.82 cm2/m2) in women. The median IMAC was −0.426 (range, −0.079–−0.968) in men and −0.359 (range, −0.079–−0.671) in women. Based on the PMI, IMAC, and other patient factors, factors associated with NAC-DCF postoperative survival were identified using multivariate Cox regression analysis. A high IMAC was significantly related to overall survival after surgery (p = 0.005, hazard ratio 2.699). A comparison of Kaplan–Meier curves showed that the 5-year survival rate was 76.5% in the low IMAC group and 42.7% in the high IMAC group (log-rank test; p = 0.001). A low IMAC was associated with good survival outcomes and was an independent prognostic factor in patients with cStage II/III ESCC who were treated with the NAC-DCF regimen and underwent surgical resection.

Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia

ObjectiveNRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC. DesignWe performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. The mechanism of action of one compound was explored by biochemical assays. ResultsUsing high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified concentrations. We then validated two of these compounds, pyrimethamine and mitoxantrone, by demonstrating their dose- and time-dependent inhibitory effects on the expression of NRF2 and its target genes in two NRF2Mut human ESCC cells (KYSE70 and KYSE180). RNAseq and qPCR confirmed the suppression of global NRF2 signaling by these two compounds. Mechanistically, pyrimethamine reduced NRF2 half-life by promoting NRF2 ubiquitination and degradation in KYSE70 and KYSE180 cells. Expression of an Nrf2E79Q allele in mouse esophageal epithelium (Sox2CreER;LSL-Nrf2E79Q/+) resulted in an NRF2high phenotype, which included squamous hyperplasia, hyperkeratinization, and hyperactive glycolysis. Treatment with pyrimethamine (30 mg/kg/day, p.o.) suppressed the NRF2high esophageal phenotype with no observed toxicity. ConclusionWe have identified and validated pyrimethamine as an NRF2 inhibitor that may be rapidly tested in the clinic for NRF2high ESCC.

Neoadjuvant Triplet Chemotherapy with Docetaxel, Cisplatin plus 5-Fluorouracil versus Docetaxel, Cisplatin plus S-1 for Advanced Esophageal Squamous cell Carcinoma: Propensity Score Matched Analysis

Introduction: This study examines whether neoadjuvant docetaxel, cisplatin plus S-1 (DCS) therapy is superior to docetaxel, cisplatin plus 5-fluorouracil (DCF) therapy for resectable advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients diagnosed with resectable advanced ESCC at our hospital between January 2010 and December 2019 underwent either neoadjuvant DCF therapy or DCS therapy, followed by radical esophagectomy. Prior to August 2014, we usually used neoadjuvant DCF therapy; we then completely transitioned to using neoadjuvant DCS therapy. Results: A total of 144 patients received one of these triplet regimens as neoadjuvant chemotherapy: DCF therapy to 67 patients and DCS therapy to 77 patients. After propensity score matching, 55 patients in each group were selected as matched cohorts. There was no significant difference between the groups in complete response (DCF = 7.3%, DCS = 9.1%) or in partial response (DCF = 45.4%, DCS = 52.7%). The pathological response rate was 23.8% for grade 2 and 18.2% for grade 3 in the DCF group, compared with 30.9% and 14.5% in the DCS group. Independent predictive factors for recurrence-free survival were poor clinical response and pathological response ≤1b. Independent prognostic factors for overall survival were poor clinical response, anastomotic leakage, and pathological response ≤1b. Duration of hospital stays in the DCS group was significantly shorter than those of the DCF group (6.0 vs. 15.0 days, p < 0.001). Expenses of drug and hospitalization for the neoadjuvant chemotherapy in the DCS group were also significantly lower than those of the DCF group (265.7 vs. 550.3 USD, p < 0.001). Conclusions: Neoadjuvant DCS therapy for resectable advanced ESCC did not result in significantly higher clinical and pathological response than neoadjuvant DCF therapy. However, neoadjuvant DCS therapy for resectable ESCC required comparatively shorter hospital stays and incurred lower costs, making it an attractive therapeutic option.