OncoTargets and therapy最新文献

Patient-derived organoids (PDOs) are emerging as a potential preclinical tool in assessing cancer patients' responses to various therapies. Here, we first described a case of invasive ductal breast carcinoma with lung and liver metastases who obtained efficient response to the sensitive drugs identified by PDOs. A 54-year-old woman came to hospital with the chief complaint of an unpainful mass in the right breast. In combination with relevant examinations, she was diagnosed with cT3N1M0 breast cancer with HER2 amplification, but developed lung and liver metastases after use of multiple therapies. After treatment with erebulin, carboplatin and inetetamab sensitive revealed by the organoid drug sensitivity testing, partial response in lung metastasis and stable disease in liver metastasis were achieved. This typical case suggests that for the individual patients with advanced refractory breast cancer, especially those exhausting the standard treatment options, the PDOs may serve as an effective model for assessing individual drug sensitivity to optimize treatment decisions and improve treatment response.

Purpose: This study aimed to evaluate the clinical utility of a pan-cancer circulating tumor DNA (ctDNA) next-generation sequencing (NGS) panel for predicting treatment response and progression-free survival (PFS) in patients with advanced solid tumors.

Patients and methods: A total of 41 patients with advanced solid tumors, including gastric cancer (n=13), non-small cell lung cancer (n=10), head and neck cancer (n=9), esophageal cancer (n=7), breast cancer (n=1), and colon cancer (n=1), were prospectively enrolled and included in the analysis. ctDNA was analyzed at three time points: pretreatment (41 patients), post-treatment evaluation (37 patients), and follow-up (18 patients).

Results: Among 41 patients analyzed at pretreatment, 35 (85.4%) exhibited tier 1 or 2 somatic variants in ctDNA, with TP53 being the most frequently mutated gene. At the post-treatment evaluation, ctDNA was assessed in 37 patients (3 with rapid deterioration and 1 lost to follow-up were not evaluable). Newly emerging variants after treatment were strongly associated with poor clinical outcomes. Consistent with the Kaplan-Meier analysis, Cox proportional hazards regression confirmed that post-treatment ctDNA positivity was significantly associated with inferior PFS (HR 10.5, 95% CI 1.4-80.0, P=0.024). At follow-up, 18 patients were evaluable, while the others were not due to follow-up loss, rapid deterioration, or study termination. ctDNA positivity at post-treatment evaluation was significantly associated with shorter PFS (median PFS, 5.0 months [95% CI: 2.0-12.0] vs not reached; HR, 4.87; 95% CI: 1.69-14.09; P = 0.0035).

Conclusion: Longitudinal monitoring of ctDNA using a pan-cancer NGS panel provides meaningful prognostic information in patients with advanced cancers. Post-treatment ctDNA dynamics may better reflect disease progression than baseline ctDNA status alone, highlighting the need for further validation in larger cohorts, particularly in gastric, lung, head and neck, and esophageal cancers.

Background: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis, highlighting the need for novel therapeutic approaches. Vimentin plays a critical role in cancer cell motility, with elevated expression observed in various cancers. This study aimed to evaluate the effects of L-sarcolysine (L-S) on the migration and adhesion of U-87 cells, with a particular focus on vimentin.

Methods: VIM expression and its prognostic significance were assessed in GBM tissue samples and cells. Molecular docking was performed to elucidate the binding interactions between L-S and vimentin, with emphasis on phosphorylation sites. Experimentally, the effects of L-S on viability, proliferation, apoptosis, migration, adhesion, and gene expression were evaluated in U-87 cells.

Results and conclusion: Upregulation of VIM was detected in both GBM tissues and U-87 cells. Molecular docking demonstrated that L-S interacts with vimentin at key residues involved in filament stabilization, including Ser39. In vitro assays showed that L-S significantly inhibited U-87 cell migration (p < 0.01), enhanced cell adhesion to the ECM (p < 0.01), and modulated VIM expression (p < 0.05). Collectively, these findings underscore the potential of L-S as an effective anti-migratory agent and highlight innovative therapeutic strategies targeting intermediate filaments.

Purpose: Colorectal cancer (CRC) is a highly prevalent malignant tumor worldwide, and the emergence of immune checkpoint inhibitors (ICIs) has changed CRC immunotherapy. This systematic review aims to provide a comprehensive overview of registered clinical trials on ICIs in CRC worldwide, with a focus on major molecular targets, combination therapy strategies, geographic distribution patterns, and future directions for precision immunotherapy.

Methods: All clinical trials related to ICIs in CRC were retrieved. Trials were screened according to inclusion and exclusion criteria, and core information such as trial phase, conducting country, mechanism targets, and combination therapy, was systematically organized for retrospective and trend analyses.

Results: A total of 1,479 eligible clinical trials were included. There has been a steady increase in the number of registered trials, with Phase II trials being the most numerous. The United States and China lead globally in the number of trials reported. Key research targets included PD-1, PD-L1, CTLA-4, and molecules related to the tumor microenvironment. Combination therapies involving ICIs, anti-angiogenic agents, and targeted drugs across multiple pathways emerged as a new research focus.

Conclusion: ICIs have driven the development of precision immunotherapy for CRC, and multi-target combination therapies hold promise for improving outcomes. However, clinical translation and efficacy improvements remain challenging. Future studies should focus on the mechanisms involved and accumulating clinical data to guide more effective immunotherapy strategies.

Background: The detection of tumor markers for predicting the therapeutic efficacy is relatively rare at present. The combined elevation of carcinoembryonic antigen (CEA), CA19-9, CA72-4, and CA125 and others may predict the efficacy of immunotherapy combined with chemotherapy, which is helpful for the precise screening of patients. This study aimed to investigate the correlation between serum tumor marker expression and clinical features, including stage, differentiation, primary site, and metastatic diameter. It also examined the relationship between tumor marker levels and the therapeutic efficacy in advanced gastric cancer patients.

Methods: We analyzed 327 patients with gastric or esophagogastric junction adenocarcinoma at Henan Provincial People's Hospital. CEA, CA19-9, CA125, and CA72-4 levels were categorized as negative, single-marker elevated, or multiple-marker (≥2) elevated. Clinical features and survival outcomes were evaluated.

Results: Elevated marker numbers correlated significantly with advanced clinical stage, lower differentiation, Lauren classification type, and larger metastatic diameter. Patients with stage IV disease exhibited higher marker elevations than those with earlier stages. No significant association was observed between the number of tumor elevated markers and T/N stage, primary/metastatic site, or PD-L1 combined positive score >5. After first-line chemotherapy, the objective response rate was positively correlated with elevated tumor marker numbers, single- rather than multiple-marker elevation showed better progression-free survival. In immunotherapy combined with chemotherapy, any increase in a tumor marker ≥5 times with a total metastasis diameter <6 cm, indicating better short-term efficacy.

Conclusion: Elevated serum tumor markers are associated with higher tumor burden, advanced stage, and poorer differentiation in gastric cancer, potentially serving as disease severity and treatment response predictors.

As nanotechnology advances rapidly, it has propelled nanomedicine into a revolutionary frontier for anticancer therapy. This review comprehensively analyzes the core principles, key innovations, and strategic approaches driving the development of targeted nanotherapeutics against tumors. We elucidate the distinctive properties of nanoscale drug delivery systems (eg, liposomes, polymeric nanoparticles, inorganic nanoparticles, and hybrid systems) and their capacity to be designed to surmount the constraints of traditional cancer treatments by potentially augmenting drug specificity, bioavailability, and minimizing systemic toxicity, with some nanocarriers (eg, liposomal doxorubicin) already approved for clinical use. With a focus on both the enhanced permeability and retention (EPR) effect-mediated passive targeting and ligand-based active targeting mechanisms employing peptides, aptamers, and antibodies, we investigate how these nanocarriers are engineered for efficient tumor-targeted drug delivery. The review further delves into the understanding of nano-bio interactions (eg, size-dependent cellular uptake) and their interplay with cancer biology. We discuss how this knowledge, alongside the rational design of stimuli-responsive and multifunctional "smart" nanoplatforms, informs the development of more precise and effective therapeutic strategies. Finally, we address the ongoing challenges in clinical translation, such as patient heterogeneity and physiological barriers, and emphasize that comprehending these aspects is pivotal for guiding future translational research towards the realization of truly patient-centric nanomedicines.

Introduction: This work aimed to identify m6A-related long non-coding RNAs (lncRNAs) associated with lung adenocarcinoma (LUAD) and evaluate their prognostic value and to examine the oncogenic actions of FAM83A-AS1 in LUAD.

Methods: The m6A-related lncRNAs in LUAD were identified by correlating lncRNA expression profiles with known m6A regulators using TCGA RNA-seq data. Prognostic lncRNAs were selected through univariate and multivariate Cox regression analyses and integrated into a risk model termed m6ARLSig. The model's predictive performance was assessed using Kaplan-Meier survival analysis, ROC curves, and principal component analysis. Immune infiltration and therapeutic responses were evaluated using CIBERSORT and drug sensitivity prediction. In vitro assays were conducted in A549 and A549/DDP cell lines to assess the oncogenic and drug resistance roles of FAM83A-AS1.

Results: We screened a set of m6A-related genes and identified a subset of m6A related-lncRNAs from TCGA through correlation analysis. Eight m6A-related lncRNAs were significantly associated with patient outcomes. AL606489.1 and COLCA1 functioned as independent adverse prognostic biomarkers, whereas six long non-coding RNAs served as independent favorable predictors of overall survival (OS). Eight lncRNAs were employed to develop a prognostic m6A-associated lncRNA signature (m6ARLSig). Based on personalized m6ARLSig levels, we computed a risk score for each individual and stratified the cohort into low-risk and high-risk categories. Survival analysis revealed a marked divergence in overall survival between the low- and high-risk cohorts, thereby substantiating the m6ARLSig's prognostic utility. In multivariate modeling, the m6ARLSig remained an independent predictor of prognosis. A nomogram incorporating m6ARLSig and clinicopathological parameters was constructed, providing a clinically adaptable tool for survival probability estimation. FAM83A-AS1 knockdown repressed A549 proliferation, invasion, migration, EMT, but increased apoptosis. Additionally, FAM83A-AS silence also attenuated cisplatin resistance of A549/DDP cells.

Conclusion: Collectively, we identified a novel m6ARLSig with prognostic value in LUAD. The m6ARLSig showed associations with clinicopathological parameters, immune cell infiltration, and therapeutic responses. FAM831-AS1 may play oncogenic role in LUAD.

Objective: To investigate the effects and mechanisms of human papillomavirus E6 (HPV16 E6) gene mutation on cervical cancer and cervical intraepithelial neoplasia grade I (CIN I) cell proliferation by regulating brain-derived neurotrophic factor (BDNF).

Methods: Real-time PCR was employed to measure mRNA levels of HPV16 E6 T350G, BDNF, and p53 in cervical cancer and CIN I tissues. Lentiviral vectors (pLV5-HPV16 E6 T350G and pLV5-vector) were constructed and transfected into human cervical epithelial cells. Real-time PCR validated successful infection and assessed mRNA changes induced by HPV16 E6 T350G. Western Blot was used to detect BDNF protein levels and PI3K/AKT phosphorylation. Cell proliferation was evaluated with the MTT assay, a standard method for assessing cell viability in vitro.

Results: Compared with CIN I cervical tissue, HPV16 E6 T350G and BDNF mRNA expression levels were positive in cervical cancer tissue, while p53 mRNA expression was negative; overexpression of HPV16 E6 T350G in human cervical epithelial cells upregulated BDNF mRNA and protein expression and activated its downstream signaling pathway PI3K/AKT, while reducing p53 protein expression; overexpression of HPV16 E6 T350G enhanced the proliferation ability of human cervical epithelial cells.

Conclusion: Overexpression of HPV16 E6 T350G can promote the proliferation ability of cervical cancer cells, possibly by upregulating BDNF expression to promote activation of the PI3K/AKT signaling pathway and decrease p53 expression.

Purpose: Lung cancer, particularly non-small cell lung cancer (NSCLC), is highly deadly globally. The potential carcinogenic role of p48, a long isoform of ErbB3-binding protein 1 (Ebp1), is well established in other cancers, but its impact on NSCLC remains unconfirmed.

Patients and methods: Several databases were utilized to compare Ebp1 expression in normal lung and NSCLC. Immunohistochemical staining was employed to identify Ebp1 expression in both types of tissue. The TCGA database assessed Ebp1 expression in NSCLC and its impact on overall survival. Ebp1 expression was knocked down in A549 and PC9 cells, and the impact of Ebp1 on the cell growth was tested by CCK-8, plate clone colony, soft agar colony generation assay, and cell cycle assays. Scratch, transwell, and in vivo were also used to confirm the effects of Ebp1 on Lung cancer cells migration, invasion. Western blot detection of EMT and signal pathway-related proteins.

Results: This study revealed that NSCLC had significantly higher levels of Ebp1 p48 expression. We discovered a correlation between Ebp1 p48 expression and pathological grade, lymph node metastasis, clinical stage, and overall survival (OS) using NSCLC tissue microarrays. In vitro and in vivo tumor cell growth, migration, invasion, the epithelial-mesenchymal transition (EMT) process, and cell proliferation are all markedly suppressed when Ebp1 p48 is knocked down in NSCLC cells. Moreover, PI3K and Akt phosphorylation levels were decreased by Ebp1 p48 knockdown.

Conclusion: According to these findings, Ebp1 p48 stimulated the PI3K/Akt signaling pathway in NSCLC, which in turn facilitated invasion, migration, and proliferation. As a result, in NSCLC, Ebp1 p48 may be a prospective therapeutic target as well as a predictive biomarker.

Aim: To observe the effect of vitamin C on Kidney renal clear cell carcinoma (KIRC) and investigate its mechanism.

Methods and results: Firstly, 29 vitamin C direct target proteins (DPTs) were identified by Drug Bank 5.0, and the protein-protein interaction (PPI) network and signaling pathways of vitamin C DPTs were analyzed. The results showed that vitamin C was not only related to KIRC, but also to the HIF-1 pathway. Meanwhile, the top 300 highly expressed genes of KIRC were obtained by GEPIA. Next, We compared the genes of four vitamin C targets in the PPI network with highly expressed genes in KIRC. Interestingly, these common genes are also involved in HIF-1 pathway. Additionally, we utilized RNA-Seq technology to explore the differentially expressed genes in KIRC with vitamin C compared to those not intervened. We observed that these differentially expressed genes exhibited a close association with hypoxia. Finally, we observed the inhibitory effect of Vitamin C on KIRC by Cell Counting Kit-8 (CCK8) assay, real-time quantitative PCR, Western blotting, flow cytometry, and colony formation assay, and confirmed that Vitamin C inhibits the growth of KIRC cells through the HIF-1 pathway.

Conclusion: Through bioinformatics analyses, we identified the molecular mechanism of vitamin C's role in KIRC and verified it through a series of experiments. Combined bioinformatics analysis will play an important role in future drug-disease interaction studies.