OncoTargets and therapy最新文献

Background: Several malignant tumors have been shown to overexpress aldolase A (ALDOA), a crucial enzyme in the glycolytic cycle. Though, it is still unknown how ALDOA contributes to breast cancer (BC).

Methods: Using GEPIA, TIMER, UALCAN, BC-GenExMiner v5.1 database, and immunohistochemistry on 96 BC patients, the expression of ALDOA was investigated. The correlation between ALDOA expression and the prognosis was evaluated by employing the Kaplan-Meier (KM) plotter in breast cancer patients.

Results: The expression of ALDOA mRNA was higher in BC compared to the normal tissues. Certain subtypes of BC showed higher ALDOA expression, including micropapillary, luminal B, non-basal-like, non-triple negative breast cancer (TNBC), and luminal androgen receptor (LAR). Overexpression of ALDOA was related to the presence of lymph node metastasis (LNM), older age, high Ki67 expression, estrogen receptor (ER) and progesterone receptor (PR) positivity, and advanced Scarff-Bloom-Richardson (SBR) and Nottingham Prognostic Index (NPI) grades, while decreased ALDOA mRNA levels were observed in TNBC and basal-like BC. KM plotter showed that higher ALDOA mRNA levels predicted worse overall survival (OS), relapse-free survival (RFS), and distant metastasis-free survival (DMFS) overall. However, in BC patients with LNM, higher ALDOA levels correlated to better DMFS.

Conclusion: ALDOA was a crucial prognostic factor required for BC advancement, indicating a possible target for BC treatment.

Lung neuroendocrine tumors (NETs) are well-differentiated neuroendocrine neoplasms of lung origin, including typical and atypical carcinoids (ACs). Therapeutic options for this rare disease are limited in daily clinical practice. Immune-checkpoint inhibitors (ICIs) are under clinical investigation. Here, we report a systematic reappraisal about ICIs results in lung NETs. We reviewed articles on observational or interventional studies that reported efficacy data of ICIs in lung NETs. Case reports and studies with insufficient data were excluded from the analysis. We searched the electronic databases Medline, Embase, Web of Science, and Cochrane Library up to May 2024. Two investigators independently screened the identified records and assessed studies quality. We summarized the results descriptively and in a meta-analysis of ORR according to the type of intervention. The search retrieved 1344 records. After selection, we included 11 studies in the meta-analysis of ORR, with a total of 128 adult patients with lung NET (25% ACs) that were progressing after at least one line of systemic therapy, including treatment with somatostatin analogs. Ten studies were Phase II, and 1 study was phase Ib. The summary ORR was 14.7% (95% CI, 5.8-32.2), 44.4% (27.2-63.1) for ACs. Subgroup analysis by intervention types showed a trend for lower ORR of lung NETs treated with ICI monotherapy (ORR: 2.7%; 0.0-63.7) compared with combinations (p-value: 0.056). The combination of temozolomide plus nivolumab showed the highest ORR (66.7%; 33.3-88.9). The median OS (reported in 2 studies) was not reached. Safety was consistent with historical data of ICIs. Our work suggests that ICIs are a promising treatment for patients with lung NETs, especially ACs, and warrant further investigation in more focused studies.

ORMDL proteins (ORMDL1, ORMDL2, ORMDL3) are transmembrane proteins in the endoplasmic reticulum (ER) that regulate sphingolipid metabolism, maintain ER homeostasis, and modulate cellular stress responses. They influence cell proliferation, apoptosis, and metabolic balance. Recent studies have highlighted the altered expression and function of ORMDL proteins in various tumors, including breast cancer, DLBCL, colorectal cancer, and lung cancer. ORMDLs negatively regulate serine palmitoyltransferase (SPT), affecting ceramide and sphingolipid metabolism, which plays a key role in tumor cell proliferation, invasiveness, and resistance to therapy. The dysregulation of ORMDL expression may disrupt sphingolipid metabolism, trigger ER stress, and impair autophagy. Investigating ORMDL functions in cancer could lead to novel insights into tumor development and progression. ORMDL expression may serve as a potential biomarker for cancer diagnosis, prognosis, and therapeutic response prediction. Targeting ORMDL or its metabolic networks offers promising strategies for cancer therapy. Although research on ORMDLs is still in its early stages, further studies are needed to explore their roles in the tumor microenvironment, interactions with the immune system, and applications in personalized medicine. A deeper understanding of ORMDL proteins will enhance tumor diagnosis, treatment, and the development of new therapeutic approaches.

Background: Internal tandem duplications (FLT3-ITDs) in the FLT3 gene constitute a key driver mutation in acute myeloid leukemia (AML), strongly associated with poor prognosis and therapeutic resistance. Although general-purpose structural variant callers such as Sniffles have been used to detect FLT3-ITDs, their limitations in resolving clonal diversity and low-frequency variants can lead to underrepresentation of minor clones. These shortcomings highlight the need for a dedicated bioinformatics pipeline.

Materials and methods: We developed a custom clustering-based pipeline to overcome the constraints of generic SV callers, leveraging Oxford Nanopore's MinION for sequencing. Our method focuses on FLT3-ITDs by grouping near-identical insertions into biologically meaningful subclones, thereby allowing accurate variant detection of even low-frequency events. The pipeline was benchmarked against capillary electrophoresis (CE) and Sniffles at various thresholds (including 10%, 20%, and 50% allele-frequency cutoffs), with results validated via IGV inspection and cross-mapping.

Results: The pipeline successfully detected FLT3-ITDs across all tested samples, including low-frequency variants and diverse subclones that Sniffles overlooked. Analyses uncovered complex multiclonal architectures composed of dominant clones (~20-25% of reads) plus multiple minor subclones differing in length, sequence, and breakpoint. Crucially, our approach identified duplications as short as 15 bp-events often dismissed by conventional SV callers. Comparative analyses showed that Sniffles failed to call several biologically validated ITDs detected by our custom pipeline.

Conclusion: Third-generation sequencing combined with a tailored clustering strategy enhances the detection of FLT3-ITDs and clonal diversity in AML compared to generic variant callers. This method provides critical insights into subclonal populations driving relapse and therapeutic resistance-particularly in relapsed/refractory AML-underscoring the importance of specialized pipelines for precision medicine in leukemia.

Lung adenocarcinoma (ADC) harboring epidermal growth factor receptor (EGFR) mutations rarely transforms into squamous cell carcinoma (SCC) following resistance to targeted therapy. Here, we present a case of EGFR-positive ADC that transformed into EGFR-negative SCC after developing resistance to EGFR tyrosine kinase inhibitors (TKIs). The patient experienced progressive disease after one cycle of chemotherapy and subsequently underwent five courses of tislelizumab combined with chemotherapy. Although the primary tumor showed a partial response to this combined regimen, intracranial metastases continued to progress, ultimately leading to the patient's death. Notably, the patient survived for 8 months after SCC transformation with immuno-chemotherapy, a significantly longer duration than the previously reported median survival of 3.5 months. This case underscores the occurrence of genomic instability, histological transformation, and dissociated response (DR) following treatment with EGFR-TKIs in EGFR-positive lung ADC. We hypothesize that these phenomena may be driven by tumor heterogeneity and the dynamic variability within the tumor microenvironment (TME).

Background: ctDNA is a non-invasive and convenient method for detecting EGFR mutations in non-small cell lung cancer (NSCLC). However, its sensitivity is lower than that of tissue-based testing. To enhance ctDNA detection efficiency, we identified the patient population most suitable for ctDNA testing, assessed the relationship between ctDNA and tumor markers, and examined the clinical significance of ctDNA in medical practice.

Methods: A single-center retrospective study was conducted, including 135 patients with NSCLC who underwent histological and liquid Super-ARMS tests. Of these, 92 patients with EGFR mutations detected in both tumor tissue and plasma were classified into the EGFR^{t+, p+} group, while 43 patients with EGFR mutations detected only in tumor tissue were classified into the EGFR^{t+, p-} group. The clinical features and outcomes between these two groups were compared.

Results: The positivity rate of Super-ARMS test was 68.1% (92/135). The presence of EGFR^{t+, p+} in the Super-ARMS test was significantly associated with pleural effusion, bone, liver, and multiple organ metastases. Compared to the EGFR^{t+, p+} group, the EGFR^{t+, p-} group had a significantly better PFS (P < 0.01). Carcinoembryonic antigen (CEA) levels demonstrated a strong predictive value for identifying plasma EGFR-mutated patients (AUC 0.828, sensitivity 68.8%, specificity 84.4%), while Maximum Standardized Uptake Value (SUV_max) also showed diagnostic value for plasma EGFR-mutated patients (AUC 0.78). Additionally, combination of TP53 and EGFR mutations in plasma provided improved risk stratification for PFS (P < 0.001).

Conclusion: Patients exhibiting metastasis, elevated levels of tumor markers and SUV_max are more suitable for plasma EGFR mutation testing in clinical NSCLC management. Moreover, a positive plasma ctDNA test not only guides targeted therapy but also predicts a worse prognosis.

Inflammatory bowel disease (IBD) is a family of chronic inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC). Among the serious malignancies that can arise from IBD, colorectal cancer is particularly prevalent. Individuals suffering from both IBD and CRC often endure similar symptoms, which include diarrhea, rectal bleeding, abdominal discomfort, weight decline, and profound exhaustion. Sanyeqing is a traditional herbaceous medicinal plant with anti-tumor, anti-inflammatory, analgesic, heat-clearing, detoxifying, and liver-protecting effects. Here, we summarize the possible molecular mechanisms of IBD and CRC, and summarize the potential role of Sanyeqing in clinical therapy for IBD and CRC. Investigating the etiology of enteritis and intestinal cancer, as well as exploring Sanyeqing's potential as a preventive and therapeutic agent, is of paramount importance in the battle against these diseases.

Background: Precocious brain metastasis in lung cancer, diagnosed through surgical resection before primary lung cancer detection, represents a unique clinical scenario with limited research. This study aims to investigate the clinical characteristics, prognosis, and the impact of different treatments on survival outcomes in this distinct population.

Materials and methods: We retrospectively analyzed clinical outcomes of lung cancer patients newly diagnosed following brain metastasis decompression surgery in our institute, over a period from July 2012 to May 2023. Patient demographics including gender, age, surgical approach, pathological findings, receipt of radiotherapy, systemic treatment modalities, and presence of druggable mutations were documented. Druggable mutations were defined as actionable genetic alterations (AGAs) detected in patients for which corresponding targeted therapeutic agents were available.

Results: Among 64 patients analyzed, 53 (82.8%) were diagnosed with adenocarcinoma; 38 (59.4%) harbored druggable mutations. There was only one patient with small cell carcinoma in this series. Types of druggable mutations were discussed in the study. The clinical stage was IVB among 38 (59.4%) patients. Forty-nine (76.6%) patients had metastatic brain lesions with number ≦3. Thirty-five (54.7%) patients received post-operative radiotherapy. The cohort's median overall survival (OS) was 19.6 months. Patients with druggable mutations had an OS longer than patients without druggable mutation (46.0 vs 14.5 months, Log rank test p =0.004). Among patients with druggable mutations, we found no difference in characteristics between patients with and without post-operative cranial radiotherapy. Patients receiving post-operative cranial radiotherapy did not show significantly better clinical efficacy than patients without radiotherapy (adjusted hazard ratio: 0.68, 95% confidence interval 0.16 to 2.91).

Conclusion: In patients with precocious brain metastases from lung cancer, the presence of druggable mutations and subsequent targeted therapy significantly extended survival, whereas post-operative brain radiotherapy may not confer additional survival benefits. These findings highlight the importance of molecular profiling and targeted therapy in this unique patient population.

Background: Disulfidptosis, a novel pattern of regulatory cell death, provides a valuable opportunity to gain deeper comprehension of tumor pathogenesis and treatment strategies. However, its biological mechanism in esophageal squamous cell carcinoma (ESCC) has yet to be completely elucidated.

Materials and methods: From the Gene Expression Omnibus (GEO) GSE53625 dataset, we obtained RNA-seq data and clinical information. An analysis of Pearson correlation was utilized to screen disulfidptosis-related lncRNAs (DRLs), followed by LASSO and multivariate Cox regression analysis to construct a prognostic signature. The reliability and accuracy of this signature were verified on internal validation sets, including training (n= 90), testing (n= 89), and GSE53625 entire (n= 179) sets, as well as external sets, including TCGA-ESCC (n= 81) and GSE53624 (n= 119) sets. Additionally, mutation data comes from TCGA database was utilized for validating tumor mutation burden (TMB) analysis. In cell lines, an analysis of lncRNA differential expression was conducted using qRT-PCR.

Results: Ultimately, six DRLs were utilized to construct a prognostic signature. Across all sets, Kaplan-Meier analysis indicated that high-risk ESCC patients have a poorer prognosis (p < 0.05), and ROC analysis showed that the AUC values at 1, 3, and 5 years all exceeded 0.6. Moreover, disparities were observed in immune phenotype scores, tumor infiltration of immune cells, functional enrichment, TIDE score, immune function, and TMB among the two risk groups. Additionally, individuals at high risk showed higher sensitivity to erlotinib, acetalax, gefitinib, lapatinib, sapitinib, and afatinib.

Conclusion: Through bioinformatics analysis, a novel and robust DRLs signature for ESCC was established, providing new insights into the prognosis prediction and potential treatment strategies. Nevertheless, this study is retrospective and relies on public databases, with a limited sample size within the datasets. In the future, it is essential to conduct more extensive validation of the prognostic value and efficacy in real ESCC cohorts.

Background: Colorectal cancer (CRC) is a significant contributor to cancer-related mortality globally. Despite the availability of treatments such as surgery, chemotherapy, and radiotherapy, these interventions are often accompanied by severe side effects and suboptimal patient outcomes. Recent studies have suggested that lidocaine, a widely used local anesthetic, may possess anti-tumor properties in various cancer types. This study aims to explore the impact of lidocaine on CRC cell lines, HCT 116 and SW480, to evaluate its potential as a therapeutic agent.

Methods: In vitro assays were conducted to assess the effect of lidocaine on the proliferation, migration, and invasion of CRC cells. The suppression of cell proliferation and induction of apoptosis were confirmed using colony formation, EdU, and TUNEL assays. RNA sequencing was performed on lidocaine-treated HCT 116 cells to identify differentially expressed genes and enriched biological pathways. A prognostic signature based on 16 genes was developed and validated using clinical data.

Results: Lidocaine significantly inhibited the proliferation, migration, and invasion of CRC cells in a dose-dependent manner. The assays confirmed that lidocaine suppressed cell proliferation and induced apoptosis. RNA sequencing revealed 8002 differentially expressed genes in lidocaine-treated HCT 116 cells, with significant enrichment of key pathways such as the estrogen signaling pathway and MAPK pathway. A prognostic signature based on 16 genes was developed and validated, providing a predictive model for patient survival. These findings suggest that lidocaine has potential as a therapeutic agent for CRC treatment, although further in vivo studies are required to clarify its mechanisms and optimize its clinical application.