Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing

Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma(HNSCC)using single-cell and bulk RNA-sequencing data.Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes(DEGs)between nivolumab resistant and nivolumab sensitive patients using R software.The Least Absolute Shrinkage Selection Operator(LASSO)regression and Recursive Feature Elimination(RFE)algorithm were performed to identify key genes associated with nivolumab resistance.Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses.The relationships of key genes with immune cell infiltration,differentation trajectory,dynamic gene expression profiles,and ligand-receptor interaction were explored.Results We found 83 DEGs.They were mainly enriched in T-cell differentiation,PD-1 and PD-L1 checkpoint,and T-cell receptor pathways.Among six key genes identified using machine learning algorithms,only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy(P<0.05).The high PPP1R14A gene expression group had lower immune score(P<0.01),higher expression of immunosuppressive factors(such as PDCD1,CTLA4,and PDCD1LG2)(r>0,P<0.05),lower differentiation of infiltrated immune cells(P<0.05),and a higher degree of interaction between HLA and CD4(P<0.05).Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients.Therefore,PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

Nanomaterials for refining tumor microenvironment and enhancing therapy in head and neck squamous cell carcinoma: a review

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.

Advanced lung adenocarcinoma with EGFR 19-del mutation transforms into squamous cell carcinoma after EGFR tyrosine kinase inhibitor treatment

In this editorial we comment on the article by Ji et al.We focus specifically on the EGFR tyrosine kinase inhibitor(EGFR-TKI)treatment and the development of drug resistance to EGFR-TKIs.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is a DUB involved in con-trolling protein deubiquitination and influencing critical cellular processes in cancer.AIM To investigate the impact of JOSD2 on the progression of ESCC.METHODS Bioinformatic analyses were employed to explore the expression,prognosis,and enriched pathways associated with JOSD2 in ESCC.Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines(KYSE30 and RESULTS )Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues,which was associated with poor prognosis.Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells.JOSD2 knockdown inhibited ESCC cell activity,including proliferation and colony-forming ability.Moreover,JOSD2 knockdown decreased the drug resistance and migration of ESCC cells,while JOSD2 overexpression enhanced these phenotypes.In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC.Mechanistically,JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways.Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2,which identified the four primary proteins that bind to JOSD2,namely USP47,IGKV2D-29,HSP90AB1,and PRMT5.CONCLUSION JOSD2 plays a crucial role in enhancing the proliferation,migration,and drug resistance of ESCC,suggesting that JOSD2 is a potential therapeutic target in 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 comprehen-sive 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.

Long noncoding RNA steroid receptor RNA activator 1 inhibits proliferation and glycolysis of esophageal squamous cell carcinoma

BACKGROUND The clinical effects and detailed roles of long non-coding RNA(LncRNA)steroid receptor RNA activator 1(SRA1)in esophageal squamous cell carcinoma(ESCC)remain ambiguous.In the present study,the complementary sites between lncRNA SRA1,miRNA-363-5p,and phospholysine phosphohistidine inorganic pyrophosphate phosphatase(LHPP)predicted via bioinformatics analysis stimulated us to hypothesize that miRNA-363-5p/LHPP axis might be required for SRA1-mediated ESCC progression.AIM To investigate the molecular events of SRA1 in the malignant behavior in ESCC.METHODS Thirty-eight ESCC tissues and paired adjacent normal tissues were acquired.SRA1 expression was detected in ESCC tissues and cell lines using quantitative reverse transcription-polymerase chain reaction.Cell counting Kit-8 assay,transwell invasion assay,glycolysis assay,and xenograft tumor model were performed to address the malignant biological behaviors of ESCC cells after the introduction of SRA1.The t-test and theχ2 test were used for comparison between groups.Survival curve analysis was performed using the Kaplan-Meier method.RESULTS SRA1 downregulation was identified in ESCC.ESCC patients exhibiting a low SRA1 expression faced shorter overall survival than those with a high SRA1 expression.The introduction of SRA1 inhibited cell proliferation,glucose uptake,and lactate production in ESCC.In vivo,the growth of ESCC was hindered by SRA1 overexpression.Then,SRA1 overexpresses the LHPP by inhibiting miRNA-363-5p.Lastly,the introduction of small interfering RNA si-LHPP or miRNA-363-5p mimic could abrogate the inhibition roles triggered by SRA1.CONCLUSION SRA1 inhibits the oncogenicity of ESCC via miRNA-363-5p/LHPP axis.The SRA1/miRNA-363-5p/LHPP pathway may be a therapeutic target for ESCC.

Application of single-cell RNA sequencing in head and neck squamous cell carcinoma

Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells’ expression programs and differentiation tracks. The studies of immune microenvironment allowed us to distinguish immune cell subpopulations, the extensive expression of immune checkpoints, and the complex crosstalk network between immune cells and non-immune cells. For cancerassociated fibroblasts(CAFs), single-cell RNA sequencing had made an irreplaceable contribution to the exploration of their differentiation status, specific CAFs markers, and the interaction with tumor cells and immune cells. In addition, we demonstrated in detail how single-cell RNA sequencing explored the HNSCC epithelial-tomesenchymal transition(EMT) model and the mechanism of drug resistance, as well as its clinical value.

Glucocorticoid reduces the efficacy of afatinib on the head and neck squamous cell carcinoma

Glucocorticoids(GC)are widely used to counter the adverse events during cancer therapy;nonetheless,previous studies pointed out that GC may reduce the efficacy of chemotherapy on cancer cells,especially in epidermal growth factor receptor(EGFR)-targeted therapy of head and neck squamous cell carcinoma(HNSCC)remaining to be elucidated.The primary aim of the present study was to probe into the GC-induced resistance of EGFR-targeted drug afatinib and the underlying mechanism.HNSCC cell lines(HSC-3,SCC-25,SCC-9,and H-400)and the human oral keratinocyte(HOK)cell lines were assessed for GC receptor(GR)expression.The promoting tumor growth effect of GC was evaluated by the CCK-8 assay and flow cytometry.Levels of signaling pathways participants GR,mTOR,and EGFR were determined by quantitative polymerase chain reaction and western blotting.GC increased the proliferation of HNSCC cells in a GR-dependent manner and promoted AKT/mTOR signaling.But GC failed in counteracting the inhibition of rapamycin in the mTOR signaling pathway.Besides,GC also induced resistance to EGFR-targeted drug afatinib through AKT/mTOR instead of the EGFR/ERK signaling pathway.Thus,GCs reduce the efficacy of afatinib on HNSCC,implicating a cautious use of glucocorticoids in clinical practice.

Personalized targeted therapy for esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial.

Boron neutron capture therapy: moving towards targeted therapy for locally recurrent head and neck squamous cell carcinoma

Locally recurrent head and neck squamous cell carcinoma(HNSCC)is often unresectable,and a repeat course of radiotherapy is associated with incremental toxicities.Boron neutron capture therapy(BNCT)is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues.However,the relationships among the dose resulting from BNCT,tumor response to BNCT,and survival are not completely understood.Recently,a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival.In this article,the findings,strengths and limitations of this study are discussed in depth,and the significance of the study and motivations for future research are highlighted.

Changing the paradigm：the potential for targeted therapy in laryngeal squamous cell carcinoma

Laryngeal squamous cell carcinoma(LSCC) remains a highly morbid and fatal disease. Historically, it has been a model example for organ preservation and treatment stratification paradigms. Unfortunately, survival for LSCC has stagnated over the past few decades. As the era of next-generation sequencing and personalized treatment for cancer approaches, LSCC may be an ideal disease for consideration of further treatment stratification and personalization. Here, we will discuss the important history of LSCC as a model system for organ preservation, unique and potentially targetable genetic signatures of LSCC, and methods for bringing stratified, personalized treatment strategies to the 21^(st) century.

IR780 loaded hollow MnO_(2) nanoparticles for dual-mode imaging and enhanced photodynamic therapy of oral squamous cell carcinoma

Photodynamic therapy(PDT)has emerged as a novel therapeutic modality for cancer treatment,but its therapeutic efficacy is severely limited by the hypoxic tumor microenvironment(TME).Here we designed an innovative multifunctional nano-platform which consists of a hollow MnO_(2) shell and internal photosensitizer IR780.It is not only used for multimodal imaging of oral squamous cell carcinoma(OSCC),but also for adjustment hypoxic TME to enhance cancer treatment.Hollow MnO_(2) can promote decomposition of tumor endogenous H2O2 to relieve tumor hypoxia,thereby enhancing the effect of photodynamic therapy.Photosensitizer IR780 generates singlet oxygen under laser irradiation to kill tumor cells,playing photodynamic effect,can also act as the contrast agents for photoacoustic and fluorescence multiple imaging,providing potential imaging capability for cancer therapeutic guidance and monitoring.Our research results in this article show that HMnO_(2)-IR780 nanocomposite exhibits good biocompatibility and nontoxicity,strong PA/FL imaging contrast,excellent oxygen production capacity and outstanding photodynamic therapy effect.This finding provides a new idea for multimodal imaging-guided nanotherapy for OSCC.

Proton beam therapy of periorbital sinonasal squamous cell carcinoma: Two case reports and review of literature

BACKGROUND Sinonasal malignancies are rare but demanding due to complex anatomy,usually late diagnosis,and inconsistent therapy strategy based on multimodality approaches.Squamous cell carcinoma(SCC)is the most common histology,with poorer prognosis.In the setting of orbital invasion,an orbital exenteration may be required.However,in case of primary rejection of disfiguring surgery or unresectable disease,proton beam therapy(PBT)should be largely considered,allowing for better sparing of neighboring critical structures and improved outcomes by dose escalation.CASE SUMMARY A 62-year-old male presented with a recurrent SCC in the nasal septum abutting frontal skull base and bilateral orbits at 7 mo after primary partial nasal amputation.Because of refusal of face-deforming surgery and considerable adverse effects of conventional radiotherapy,the patient underwent a PBT by hyperfractionated accelerated scheme,resulting in complete response and moderate toxicities.After 2 years,a nasal reconstruction was implemented with satisfactory appearance and recurrence-freedom to date.Another patient with an initially extended sinonasal SCC,invading right orbit and facial soft tissue,declined an orbital exenteration and was treated with a normofractionated PBT to the gross tumor and elective cervical lymphatics.The follow-up showed a continuous tumor remission with reasonable late toxicities,such as cataract and telangiectasia on the right.Despite T4a stage and disapproval of concurrent chemotherapy owing to individual choice,both patients still achieved outstanding treatment outcomes with PBT alone.CONCLUSION PBT enabled orbit preservation and excellent tumor control without severe adverse effects on both presented patients with locally advanced sinonasal SCC.

Integrated bioinformatics analysis of potential biomarkers and candidate drugs of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC),the major subtype of esophageal carcinoma(ESCA),is one of the most lethal malignancies worldwide.This study aimed to identify potential biomarkers and/or therapeutic targets for ESCC.The datasets GSE44021,GSE77861,GSE20347,and GSE29001 retrieved from the Gene Expression Omnibus(GEO)database contained 117 ESCC tissues and 109 normal tissues.Differentially expressed genes(DEGs)associated with ESCC were identified using the GEO2R tool.Dysregulated pathways associated with ESCC mainly included mitotic regulation,cell cycle,ECM-receptor interaction,DNA replication,etc.The protein-protein interaction(PPI)network of overlapping DEGs was constructed and nine key genes(KGs)were identified from the complex interaction network using Degree,maximum neighborhood component(MNC),and maximal clique centrality(MCC)algorithms.Expression patterns of KGs at the transcriptional and translational levels were validated using ESCC-related data from the Cancer Genome Atlas(TCGA),Oncomine,and Human Protein Atlas(HPA)databases.Genetic alterations calculation,immune cell infiltrates evaluation,methylation analysis,prognostic analysis,transcription factors(TFs)and miRNAs regulatory networks construction,and targeted drug prediction were further performed.It was also found that the knockout of these KGs affected the survival of more than two types of ESCC cells by genome-wide CRISPR-Cas9 dropout screens.In conclusion,we identified KGs,TFs,and miRNAs with biomarker potential(e.g.,NDC80,BUB1,TOP2A,AURKA,AURKB,TTK,UBE2C,TPX2,BUB1B,E2F1,and hsa-miR-483-5p)and 23 candidate targeted drugs for ESCC by utilizing an integrated multi-omics approach.These findings provide additional insights into uncovering the molecular mechanism and improving the efficiency of clinical diagnosis and treatment for ESCC.

Monitoring disease progression and treatment efficacy with circulating tumor cells in esophageal squamous cell carcinoma: A case report

This study investigated whether changes in circulating tumor cell(CTC) numbers reflect tumor progression and treatment efficacy in esophageal squamous cell carcinoma(ESCC). A 47-year-old male patient with ESCC is presented in this case study. The patient was evaluated for a series of serum tumor markers and subjected to radiological examinations before and after surgery and during follow-up over the course of five years. In addition, the CTCs in 7.5 m L of peripheral blood were enriched by magneticactivated cell sorting negative selection and identified by immunofluorescence staining. Serum tumor markers remained within normal ranges and were discordant with imaging scans during the follow-up. Initially, one CTC was detected in the peripheral blood sample, and 14 were observed seven days after the operation. After 12 wk, subcutaneous metastases and bone metastases occurred, and the number of CTCs increased to 84. After 48 wk, lung metastases were noted, and the CTC level was 21. At 104 wk, the number of CTCs was 14, and disease recurrence was detected by positron emission tomography-computed tomography. The CTC counts were in accord with the imaging studies at several time points. The additional information provided by CTC enumeration could thus facilitate monitoring of disease status and treatment efficacy and provide support for treatment decisions.

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.

Neoadjuvant treatment for esophageal squamous cell carcinoma

Squamous cell carcinoma and adenocarcinoma are types of esophageal cancer, one of the most aggressive malignant diseases. Since both histological types present entirely different diseases with different epidemiology, pathogenesis and tumor biology, separate therapeutic strategies should be developed against each type. While surgical resection remains the dominant therapeutic intervention for patients with operable esophageal squamous cell carcinoma(ESCC), alternative strategies are actively sought to reduce the frequency of post-operative local or distant disease recurrence. Such strategies are particularly sought in the preoperative setting. Currently, the optimal management of resectable ESCC differs widely between Western and Asian countries(such as Japan). While Western countries focus on neoadjuvant or definitive chemoradiotherapy, neoadjuvant chemotherapy followed by surgery is the standard treatment in Japan. Importantly, each country and region has established its own therapeutic strategy from the results of local randomized control trials. This review discusses the current knowledge, available data and information regarding neoadjuvant treatment for operable ESCC.

Black phosphorous nanosheets−gold nanoparticles−cisplatin for photothermal/photodynamic treatment of oral squamous cell carcinoma

To improve five-year survival rate of oral squamous cell carcinoma(OSCC),the development of a novel composite material of black phosphorus nanosheets(BPNSs)and gold nanoparticles(AuNPs)for tumor treatment was carried out.The purpose of this study is to evaluate the cytostatic effects of BPNSs,AuNPs loaded with cisplatin(CDDP)on human tongue squamous cell carcinoma cells lines(SCC-9),and 7,12-dimethylbenz anthracene induced cheek squamous cell carcinoma was validated in golden hamsters animal models.The results showed that BPNSs could efficiently inhibit the metastasis and growth of OSCC compared with CDDP and AuNPs.And a combination composite of AuNPs−BPNSs loaded with CDDP could more effectively inhibit the metastasis and growth of OSCC,which might be due to the high drug-loading capacity,excellent photothermal properties and the combination of photodynamic and photothermal therapy of BPNSs and AuNPs,as well as the synergistic effects of AuNPs,BPNSs and CDDP.

Multiline treatment of advanced squamous cell carcinoma of the lung: A case report and review of the literature

BACKGROUND Squamous cell carcinoma (SCC) is one the most common subtypes of non-small cell lung cancer, yet the treatment options for it remain limited. Here, we report a case of advanced SCC and review the related literature focusing on the multiline therapy method. CASE SUMMARY We report the case of a 45-year-old man with advanced SCC who was deemed inoperable at the time of advanced SCC diagnosis. The patient had been referred to our hospital in April 2013 with complaints of a stuffy feeling in the chest, dyspnea, and pain in the right shoulder lasting for 1 mo. Physical examination found no obvious abnormalities, except for lower breath sound in the right lower lung. Laboratory data were within normal limits. Immunohistochemistry analysis of the tumor tissue showed CK5/6 (+), p63 (+), CD56 (+), and Ki-67 (+, approximately 30%), and genetic testing detected no EGFR mutation. He received a multiline treatment that included chemotherapy, radiotherapy, targeted therapy, and antiangiogenic therapy. After more than 5-year comprehensive treatment, the patient remains alive. CONCLUSION This typical case highlights the importance of appropriate multiline therapy for those patients with advanced SCC.