OncoTargets and therapy最新文献

Here, we report a case of a male patient who was initially diagnosed with stage IV driver gene-negative lung adenocarcinoma and received immune checkpoint inhibitors plus chemotherapy as first-line therapy. The patient progressed to meningeal metastasis and harbored an EGFR exon20 p.A763V mutation. A double dose of Osimertinib was recommended and the patient achieved a PFS of 10 months. This report offers evidence that Osimertinib may serve as a treatment option for patients with EGFR exon20 p.A763V mutation. In addition, dynamic spatiotemporal heterogeneity of lung cancer cells should be considered when treating patients with EGFR-positive NSCLC.

Colorectal cancer (CRC) ranks as the third most prevalent malignancy globally based on recent epidemiological studies. In China, the rising incidence and mortality rates of CRC have underscored the importance of elucidating its pathogenic mechanisms, which remain major focus in current biomedical research. Ferroptosis, a regulated cell death process driven by iron-dependent lipid peroxidation, is closely associated with disruptions in iron homeostasis, lipid metabolism, and amino acid metabolism. This unique iron-catalysed death process plays a crucial role in both tumor initiation and malignant progression by disturbing cellular redox imbalance. The cystine/glutamate antiporter SLC7A11 (also known as xCT) has been identified as a central regulator of ferroptosis susceptibility. The tumor suppressor p53 and its associated microRNAs modulate ferroptotic responses through regulation of SLC7A11 expression, forming a critical axis in oncogenic transformation and metastasis. However, the precise role of SLC7A11 in CRC-particularly its context-dependent dual functions as both a tumor promoter and a therapeutic vulnerability-remains a critical unanswered question. This review aims to systematically summarize current advances in understanding the multiple roles of SLC7A11 in CRC-related ferroptosis pathways and to evaluate emerging therapeutic strategies targeting this axis. Importantly, we also underscore the existing knowledge gaps and outline future research directions essential for leveraging this unique molecular pathway to improve patient outcomes.

Purpose: The poor prognosis of KRAS-mutant colorectal cancer is attributed to its immunosuppressive tumor microenvironment and the lack of effective targeted therapies. Transforming growth factor-β-activated kinase 1 (TAK1), serving as a critical upstream regulator of both the NF-κB and MAPK signaling pathways, promotes tumor progression through its aberrant activation. In this study, we aimed to investigate the anti-tumor and immunomodulatory effects of the TAK1 inhibitor NG25 in KRAS-mutant colorectal cancer, focusing on its impact on T cell differentiation, PD-L1 expression, and tumor immune microenvironment remodeling.

Methods: The anti-tumor and immune-enhancing effects of NG25 were evaluated through an in vitro tumor cell-lymphocyte co-culture system, and the orthotopic colorectal cancer models in both immunodeficient Balb/c nude mice and immunocompetent Balb/c mice.

Results: NG25 significantly suppressed the tumor progression in immunocompetent Balb/c mice, while concurrently increasing the spleen and thymus indices and promoting the proliferation of T and B lymphocytes. In tumor microenvironment, NG25 treatment could promote CD8⁺ T cell infiltration and increase the proportion of CD3⁺CD8⁺ T cell subsets. Mechanistic studies revealed that NG25 downregulates PD-L1 expression on both KRAS-mutant tumor cells and T cells through inhibiting TAK1/NF-κB axis. However, this regulatory effect was absent in KRAS wild-type tumor cells.

Conclusion: NG25 blocks the NF-κB signaling pathway by targeting TAK1, remodels the immunosuppressive microenvironment of KRAS-mutated colorectal cancer, reduces PD-1 expression and enhances the anti-tumor effect of CD8⁺ T cells. This study provides a theoretical basis for TAK1-targeted therapy and offers a new strategy for immunotherapy of KRAS-mutated colorectal cancer.

Background: Oncolytic virotherapy is a novel therapeutic approach in oncology that uses viruses to target and eradicate cancer cells specifically. To improve therapeutic effectiveness, we investigated the application of genetically modified oncolytic adenoviruses (OVs) engineered to express bispecific T-cell engager (BiTE) antibodies.

Methods: In particular, we engineered Ad5-delta24 to express an EpCAM-targeting BiTE under the major late promoter, yielding the recombinant virus Ad5D24-Anti-EpCAM-Anti-CD3-scFv (rOAd5-BiTE). Following infection of A549 lung cancer cells, rOAd5-BiTE promoted the expression and secretion of BiTE antibodies targeting EpCAM and CD3.

Results: In co-culture experiments, rOAd5-BiTE elicited significant T-cell activation and proliferation, characterized by increased secretion of IFN-γ and IL-2, as well as augmented cytotoxic activity from neighboring bystander cells. Moreover, the combination of rOAd5-BiTE with peripheral blood mononuclear cells (PBMCs) markedly enhanced the antitumor activity against A549 cells.

Conclusion: The results indicate that equipping OVs with BiTE molecules may address critical challenges in virotherapy by enhancing and redirecting T-cell activity within the tumor microenvironment. This strategy offers a promising avenue for developing targeted immunovirotherapy approaches for the treatment of solid tumors.

[This retracts the article DOI: 10.2147/OTT.S116509.].

Purpose: Transcription factor MYB proto-oncogene like 2 (MYBL2) is involved in cell cycle regulation and proliferation, and it has been implicated in various cancers. However, its expression pattern and clinical significance in hepatocellular carcinoma (HCC) are unclear. Therefore, the aim of this study was to evaluate the tissue expression of MYBL2 in patients with HCC and evaluate associations with clinicopathological factors and prognosis.

Patients and methods: We enrolled 88 patients with HCC who underwent hepatectomy from October 2023 to January 2025 and analyzed MYBL2 expressions in non-tumorous and tumorous tissue samples using immunohistochemistry. The patients were then categorized into high and low expression groups, and clinicopathological factors were compared. Cox proportional hazard regression and Kaplan-Meier survival analyses were used to explore the prognostic significance of MYBL2 expression.

Results: MYBL2 immunohistochemistry score was significantly associated with survival (p for trend = 0.038). Kaplan-Meier analysis demonstrated that those with a high MYBL2 expression were associated with lower overall survival compared to those with a low MYBL2 expression (p = 0.029). An independent association was found between high MYBL2 expression in tumorous tissues and poor overall survival (p = 0.047). However, multivariate analysis indicated that MYBL2 expression was not an independent risk factor for overall survival.

Conclusion: The results indicated an association between MYBL2 and HCC prognosis, suggesting that it could be used as a prognostic biomarker and potentially be a therapeutic target. Further research is required to clarify the molecular mechanisms by which MYBL2 drives tumor progression and to explore its potential in targeted therapy for HCC.

Therapeutic options for NSCLC with epidermal growth factor receptor exon20 insertions (EGFR ex20ins) are limited. Sunvozertinib is a novel orally EGFR inhibitor that has been approved to treat EGFR ex20ins NSCLC at second line setting. Herein, we reported an unexpected therapeutic outcome of first-line sunvozertinib treatment in a patient with stage IIIB EGFR ex20ins-positive lung adenocarcinoma (T1cN3M0). We found three months of sunvozertinib neoadjuvant treatment led to remarkable shrinkage of the primary tumor and downstaged N3 metastatic disease. A radical resection was scheduled after careful evaluation. Histological assessment of the resected tumor and lymph nodes showed a complete pathologic response. The patient was recommended to continue sunvozertinib as an adjuvant therapy, whereas he developed brain metastasis within three months after surgery. We proposed that the brain metastasis occurred as a result of sunvozertinib dose de-escalation-induced disease flare. Rechallenge with adequate dosage of sunvozertinib led to a rapid shrinkage of the brain metastasis. Our case highlighted the feasibility of sunvozertinib neoadjuvant therapy in EGFR ex20ins-positive NSCLC patient with locally advanced disease. Importantly, adjuvant therapy using an adequate dosage of sunvozertinib is pivotal to prevent disease flare and tumor recurrence.

Background: Systemic inflammation has emerged as a key determinant of prognosis in epithelial ovarian cancer (EOC). The pre-treatment C-reactive protein/albumin (CRP/Alb) ratio integrates host inflammatory and nutritional status, but its prognostic role in advanced-stage EOC remains incompletely defined.

Methods: We retrospectively analyzed 256 patients with FIGO stage III-IV high-grade serous ovarian cancer treated at a tertiary oncology center between 2010 and 2024. All patients underwent primary or interval cytoreductive surgery followed by standard platinum-based chemotherapy. Pre-treatment CRP and albumin values obtained within 14 days before therapy were used to calculate the CRP/Alb ratio. Patients were stratified according to the predefined median cut-off (2.32). Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. Cox regression models were applied for univariate and multivariate analyses.

Results: Median follow-up was 81.4 months. The median OS for the entire cohort was 58.1 months. Patients with a CRP/Alb ratio <2.32 had significantly longer OS (74.6 vs 45.6 months; p = 0.003) and PFS (24.8 vs 17.1 months; p = 0.026) compared to those with higher ratios. In multivariate analysis, a CRP/Alb ratio ≥2.32 remained an independent predictor of worse OS (HR = 1.88; 95% CI: 1.12-3.18; p = 0.018), along with age ≥65 years (HR = 2.34; p < 0.001) and ECOG performance status 2-3 (HR = 1.60; p = 0.006). Individual CRP or albumin levels did not retain prognostic significance.

Conclusion: The pre-treatment CRP/Alb ratio is a simple, accessible, and independent prognostic biomarker in advanced-stage EOC. Its integration into routine risk assessment may enhance individualized prognostication and help identify high-risk patients who could benefit from closer monitoring and tailored supportive care. Prospective multicenter validation is warranted.

Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non-small cell lung cancer (NSCLC) but can cause severe immune-related adverse events. We report a fatal case of suspected steroid-refractory autoimmune encephalitis in a 71-year-old male with squamous NSCLC, occurring 14 months after sequential ICI therapy (toripalimab, then sintilimab, followed by anlotinib-sintilimab). He presented with acute behavioral decline. Brain MRI revealed non-enhancing T2/FLAIR hyperintensities in the cerebellum and frontal lobes, with low cerebrospinal fluid (CSF) opening pressure. Diagnostic workup was negative for infections and neuronal autoantibodies. Despite aggressive immunosuppression with high-dose corticosteroids, mycophenolate mofetil, and intravenous immunoglobulin, his condition progressed to coma with diffuse cerebral edema and hydrocephalus, leading to death within 14 days. This case highlights the lethal potential of ICI-induced encephalitis, the diagnostic challenges of seronegative presentations, and the urgent need for more effective treatment strategies.

Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy with limited therapeutic options and poor prognosis. Identifying robust prognostic biomarkers and therapeutic targets is essential for improving patient outcomes. Minichromosome maintenance complex component 4 (MCM4), a DNA replication licensing factor, has been associated various malignancies, yet its involvement in HCC remains underexplored.

Methods: We performed integrative bioinformatics analyses on three public HCC datasets (GSE14520, GSE56545, and GSE84402) to identify consistently dysregulated genes. Functional enrichment analyses were conducted using GO, KEGG, and Reactome databases. PPI networks were constructed via STRING. The expression and prognostic value of MCM4 were evaluated using GEPIA, Human Protein Atlas, and KM-Plotter. Single-cell and spatial transcriptomics from the HCCDB were analyzed to explore MCM4 localization. Functional roles of MCM4 were validated in vitro using siRNA-mediated knockdown and plasmid-based overexpression in HepG2 and Huh7 cells.

Results: MCM4 was identified as a consistently upregulated gene in HCC and was associated with poor overall, disease-free, recurrence-free, and disease-specific survival. Single-cell and spatial transcriptomic analyses revealed MCM4 enrichment in proliferative tumor regions. Functional assays demonstrated that MCM4 promotes HCC cell growth, motility, invasiveness, and enhances EMT and stemness. Conversely, MCM4 knockdown attenuated these malignant phenotypes.

Conclusion: Our study establishes MCM4 as a key regulator of HCC progression and a potential prognostic biomarker. These findings suggest that MCM4 may serve as a potential target and underscore integrative and spatial transcriptomic approaches in cancer biomarker discovery.