Search Results (283)

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes. Full article

Ochratoxin A (OTA), a prevalent food contaminant, has been proposed as a potential contributor to the development of prostate cancer, although its precise mechanisms remain unclear. This study employed a comprehensive approach that integrated network toxicology, machine learning, and molecular docking to clarify the role of OTA in prostate cancer. The findings indicated that OTA interacts with 364 targets related to prostate cancer, and machine learning was employed to identify five key molecular targets as priorities (ESR1, TP53, TNF, INS, and EGFR). In conjunction with the results of a functional enrichment analysis, OTA was found to possibly facilitate cancer progression by disrupting endocrine function, activating oncogenic signaling pathways, reprogramming metabolism, and modulating the tumor microenvironment. Full article

Over recent decades, significant advancements have been made in the treatment and imaging of gliomas. Conventional imaging techniques, such as MRI and CT, play critical roles in glioma diagnosis and treatment but often fail to distinguish between tumor pseudoprogression (Psp) and radiation necrosis (RN) versus true progression (TP). Emerging fields like radiomics and radiogenomics are addressing these challenges by extracting quantitative features from medical images and correlating them with genomic data, respectively. This article will discuss several studies that show how radiomic features (RFs) can aid in better patient stratification and prognosis. Radiogenomics, particularly in predicting biomarkers such as MGMT promoter methylation and 1p/19q codeletion, shows potential in non-invasive diagnostics. Radiomics also offers tools for predicting tumor recurrence (rBT), essential for treatment management. Further research is needed to standardize these methods and integrate them into clinical practice. This review underscores radiomics and radiogenomics’ potential to revolutionize glioma management, marking a significant shift towards precision neuro-oncology. Full article

TP (tumor protein) 53 mutation status plays a critical role in cancer progression and may influence survival outcomes in non-small cell lung cancer (NSCLC) patients receiving immunotherapy. This study investigates the impact of TP53 mutation status and immunotherapy treatment on survival in NSCLC patients. This retrospective study analyzed NSCLC patients treated with pembrolizumab or ipilimumab plus nivolumab, stratified by TP53 mutation status and PD-L1 (programmed death-ligand 1) expression (<1%, 1–49%, >50%). Survival outcomes (overall survival (OS) and progression free survival (PFS) were assessed using Kaplan–Meier curves and log-rank tests, with subgroup analysis by histological subtype. In squamous cell cancer (SCC) patients, no significant differences in OS or PFS were found based on TP53 mutation status or treatment type. A trend toward improved survival was observed with pembrolizumab (p = 0.088). In adenocarcinoma patients, significant differences in OS and PFS were observed based on TP53 mutation status. Pembrolizumab showed superior survival outcomes compared to ipilimumab plus nivolumab in TP53 wild-type patients (p < 0.001). PD-L1 ≥ 1% also predicted better outcomes, especially in adenocarcinoma patients. TP53 mutation status and immunotherapy type significantly influence survival outcomes in NSCLC, particularly in adenocarcinoma patients. Pembrolizumab demonstrated superior efficacy in TP53 wild-type patients, with PD-L1 expression further refining survival predictions. These findings underscore the importance of personalized treatment strategies based on TP53 status and PD-L1 expression in NSCLC. Further studies are needed to validate these results and optimize treatment approaches. Full article

Worldwide, lung cancer is one of the most common cancers, with non-small cell lung cancer (NSCLC) including up to 80–85% of all lung cancer diagnoses. The landscape of NSCLC is characterized by a heterogeneous spectrum of gene alterations, with tyrosine kinase inhibitors (TKIs) and targeted treatments that significantly improve survival outcomes for patients with oncogene-addicted NSCLC, offering superior efficacy, and often favorable safety and tolerability profiles compared to chemotherapy-based treatments. However, the complexity of NSCLC extends to co-occurring genomic alterations or amplifications in tumor suppressors and other oncogenes, such as TP53, STK11, KEAP1, PIK3CA, RB1, and others, that significantly influence disease progression, therapeutic resistance, and clinical outcomes. These co-mutations often contribute to the development of primary and acquired resistance to targeted therapies, complicating decision-making strategies. This review provides a timely and comprehensive synthesis of current insights into co-mutations in NSCLC, with a particular focus on their clinical implications, and offers a novel perspective by integrating recent molecular insights with therapeutic challenges, addressing existing knowledge gaps through a more integrative and clinically oriented analysis of co-mutations. Advances in next-generation sequencing (NGS) and molecular profiling have enabled the identification of these co-alterations, paving the way for more personalized therapeutic approaches. However, challenges remain in interpreting the functional interplay of co-mutations and translating these insights into effective clinical interventions. This review also highlights the significance of co-mutations in shaping NSCLC biology, and discusses their impact on current therapeutic paradigms, emphasizing the need for integrative biomarker-driven approaches to improve outcomes in NSCLC. Full article

Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy with rising incidence and poor prognosis. TP53, previously identified as the most frequently mutated gene in EAC in our studies, plays a central role in tumor suppression and regulation. However, the metabolic consequences of TP53 mutations in EAC remain largely uncharacterized. We metabolically profiled three TP53-mutant EAC cell models (OE33, OE19, and FLO1) representing progressive stages of tumor differentiation and harboring distinct TP53 alterations. Our analyses revealed different metabolic phenotypes associated with TP53 status. OE33 cells predominantly use glycolytic metabolism but display limited adaptability to environmental changes, possibly due to a higher differentiation state. FLO1 cells exhibit a strong glycolytic dependence, elevated lactate production, and robust proliferation under acidic conditions, consistent with an aggressive and metastatic phenotype. OE19 cells preferentially utilize oxidative phosphorylation, demonstrated by resilience to glucose and glutamine deprivation, and ROS accumulation. These findings highlight the metabolic plasticity of EAC and suggest that TP53 mutation type might influence bioenergetic dependencies. Targeting these metabolic vulnerabilities may offer novel therapeutic avenues for personalized treatment in EAC. Full article

Background: Medullary thyroid cancer (MTC), a neuroendocrine tumor originating from thyroid parafollicular C-cells, presents therapeutic challenges, particularly in advanced stages. While RET proto-oncogene mutations are known drivers, a comprehensive understanding of the broader somatic mutation landscape is needed to identify novel therapeutic targets and improve prognostication. This study leveraged the extensive AACR Project GENIE dataset to characterize MTC genomics. Methods: A retrospective analysis of MTC samples from GENIE examined recurrent somatic mutations, demographic/survival correlations, and copy number variations using targeted sequencing data (significance: p < 0.05). Results: Among 341 samples, RET mutations predominated (75.7%, mostly M918T), followed by HRAS (10.0%) and KRAS (5.6%), with mutual exclusivity between RET and RAS alterations. Recurrent mutations included KMT2D (5.3%), CDH11 (5.3%), ATM (5.0%), and TP53 (4.1%). NOTCH1 mutations were enriched in metastatic cases (p = 0.023). Preliminary associations included sex-linked mutations (BRAF/BRCA1/KIT in females, p = 0.028), and survival (ATM associated with longer survival, p = 0.016; BARD1/BLM/UBR5/MYH11 with shorter survival, p < 0.05), though limited subgroup sizes warrant caution. Conclusions: This large-scale genomic analysis confirms the centrality of RET and RAS pathway alterations in MTC and their mutual exclusivity. The association of NOTCH1 mutations with metastasis suggests a potential role in disease progression. While findings regarding demographic and survival correlations are preliminary, they generate hypotheses for future validation. This study enhances the genomic foundation for understanding MTC and underscores the need for integrated clinico-genomic datasets to refine therapeutic approaches. Full article

Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas. Full article

Background: The N⁶-methyladenosine (m⁶A) modification of eukaryotic mRNA is the most prevalent of such epigenetic modifications and has recently been identified as a potential player in the pathogenesis and progression of hepatocellular carcinoma (HCC). With the increasing emergence of immunotherapy in the treatment of HCC, we have evaluated the potential of m⁶A-related genes in predicting overall survival and the therapeutic efficacy of immunotherapy in HCC patients. Methods: We employed transcriptomic data from TCGA-LIHC and GSE76427, comprising a total of 485 HCC patients, as the training set. Based on 23 recognized m⁶A regulators, we performed clustering analysis on HCC patients. The intersecting differentially expressed genes (DEGs) among subtypes were used in least absolute shrinkage and selection operator (LASSO) Cox and multivariate Cox regression analyses to construct the risk model. For the quantification of a risk model of HCC patients, a risk score was developed and correlated with clinical and immunological parameters. Furthermore, a single-cell transcriptomic atlas was used to analyze the relationship between model genes and immune cell subpopulations. Mechanistic studies included in vitro assays to validate the association between the m⁶A-related gene ANLN and the progression of HCC. Results: Internal (TCGA and GEO) and external validation (ICGC) suggested that an 8-gene risk score provides an accurate and stable prognostic assessment for HCC. Furthermore, the high-risk score, characterized by elevated TP53 mutation frequency, tumor mutation burden (TMB), and tumor stem cell characteristics indicated a poor prognosis. The prognostic signature was associated with immune cell infiltration in HCC. Those patients with a high-risk score had lower immune tolerance with a better prediction of the efficacy of immunotherapy. The risk model helps to assess and predict the response and prognosis of HCC patients to immune checkpoint inhibitors (ICIs). Additionally, single-cell RNA sequencing data revealed that the high-risk group had a higher proportion of T cells and fewer immunosuppressive T cells, potentially correlating with a better response to immunotherapy. Finally, in vitro experiments showed that ANLN, an m⁶A-related gene, promoted the proliferation and migration of HCC cells. Conclusions: In this study, we identified and validated an m⁶A gene signature consisting of eight genes that can be used to predict prognosis and immunotherapy efficacy in HCC patients. Full article

Introduction: Elderly patients with metastatic non-small-cell lung cancer (NSCLC) are underrepresented in clinical trials evaluating immune checkpoint inhibitors (ICIs). This study assesses the efficacy of first-line pembrolizumab monotherapy in patients with metastatic NSCLC aged ≥70 years with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50%. Materials and Methods: We retrospectively analyzed 381 patients with metastatic NSCLC without oncogenic driver mutations treated with pembrolizumab monotherapy between 2017 and 2023 at three academic centers in Central and Southeastern Europe. Clinical outcomes, including median time on treatment (mToT) and overall survival (mOS), were compared between patients aged ≥70 and <70 years. Results: Of 381 patients, 149 (39.1%) were aged ≥70. No significant differences in mToT (12.7 vs. 14.3 months; p = 0.125) or mOS (18.2 vs. 27.4 months; p = 0.124) were observed between older and younger groups. Good ECOG PS (0–1) was independently associated with longer mToT and mOS in older patients. Additionally, a history of smoking was linked to improved outcomes compared to never-smokers, suggesting potential immunogenic effects. Older patients were significantly less likely to receive second-line therapy after progression (p = 0.04). Conclusions: First-line pembrolizumab monotherapy is effective across all age groups and provides similar treatment efficacy in patients with metastatic NSCLC and a PD-L1 TPS ≥ 50%. Patients older than 70 with a smoking history and ECOG PS 0–1 derive the most benefit from this treatment modality. The adaptation of this treatment strategy for elderly patients is especially important, since only a minority of them are capable of receiving second-line therapy. Full article

Background: Increasing evidence suggests that the immunogenicity of COVID-19 mRNA vaccines might influence the efficacy of immune checkpoint inhibitors (ICIs). Current studies have not considered the impact of additional vaccinations, which are now recommended as a preventive strategy against SARS-CoV-2 infection for cancer patients receiving active treatments. Consequently, we leveraged the prospective monitoring from the Vax-On-Third study to explore whether periodic mRNA vaccine boosters administered around the start of ICIs could influence the rates of immune-related adverse events (irAEs) and survival outcomes in patients with advanced non-small cell lung cancer (NSCLC). Methods: Our study included patients with a histological diagnosis of metastatic NSCLC and available PD-L1 tumor proportion score (TPS), who had undergone at least two cycles of upfront treatment with pembrolizumab, cemiplimab, or their combination with platinum-based chemotherapy. Patients who received any additional mRNA-based vaccine doses within 60 days before to 30 days after starting ICIs accounted for the exposed cohort. Those who declined further boosters formed the reference cohort. We analyzed differences in irAE frequencies, progression-free survival (PFS), and overall survival (OS) using univariate and multivariate analyses. Results: Between 27 November 2021 and 31 March 2024, we enrolled 226 eligible patients. The exposed cohort consisted of 112 patients who had received either a third or fourth dose of tozinameran or a bivalent booster. Based on PD-L1 expression levels, 93 (41%) and 133 (59%) patients received single-agent ICIs (PD-L1 TPS ≥ 50%) or combination regimens (PD-L1 TPS < 50%), respectively. Propensity-score matching using comprehensive criteria resulted in two cohorts of 102 patients each, with an optimal balance of prognostic factors. A thorough analysis of any grade irAEs showed no significant differences between the cohorts. A longitudinal survival assessment with a median follow-up of 22.8 (95% CI 19.2–26.0) months showed no difference between the cohorts. The median PFS for the reference and exposed cohorts was 7.5 (95% CI 5.9–9.1) and 8.2 (95% CI 6.2–10.2) months, respectively (p = 0.408; HR 0.88 [95% CI 0.66–1.18]). The median OS for the reference and exposed cohorts was 10.5 (95% CI 7.9–13.0) and 13.8 (95% CI 12.0–15.5) months, respectively (p = 0.170; HR 0.81 [95% CI 0.59–1.09]). Multivariate analysis confirmed that receiving additional mRNA vaccine boosters did not significantly affect the risk of disease progression or mortality. Univariate analysis within the subgroup of patients with high PD-L1 TPS who received single-agent ICIs showed a significant OS advantage for patients in the exposed cohort (9.7 [95% CI 8.1–11.2] vs. 18.6 [95% CI 13.5–23.6] months; p = 0.034; HR 0.59 [95% CI 0.36–0.96]). Conclusion: After optimally balancing prognostic factors, regular mRNA vaccine boosters at the onset of ICIs did not impact the safety and survival of patients with advanced NSCLC. The improved outcome observed in patients with high PD-L1 expression levels aligns with previous findings and warrants further investigation. Full article

Background: Colorectal cancer is the third most common cancer worldwide, accounting for about 10% of all cancer cases. There is an urgent need to improve treatment outcomes and survival rates for colorectal cancer. Juglone is an anthraquinone with anti-inflammatory, antiviral, and anti-cancer properties that have shown promise in inhibiting tumor cell growth. Objectives: This study aims to explore the mechanism behind Juglone’s anti-cancer effects on colorectal cancer. Methods: Network pharmacology, molecular docking and molecular dynamics simulation were used to explore the specific targets of Juglone in the treatment of colorectal cancer. For in vitro validation, we used the CCK–8 (Cell Counting Kit–8) method, flow cytometry, ROS (Reactive Oxygen Species) detection, and Western blot analysis to assess the survival ability of colorectal cancer cells and validate the expression of proteins most closely associated with the pathways. Results: Network pharmacology identified TP53 as a key target of Juglone, involved in anti-tumor pathways. Molecular docking and molecular dynamics simulations showed that the p53 has strong affinity and stability with Juglone. Results from cytotoxicity experiments, flow cytometry, ROS detection, and Western blotting indicated that the anti-colorectal cancer effect of Juglone depends on concentration and is mediated by promoting intracellular ROS generation and upregulating the expression level of p53 protein, thereby inhibiting the progression of colorectal cancer. Conclusions: Juglone can achieve anti-colorectal cancer effects by increasing ROS levels and regulating the p53 protein. Full article

Background/Objectives: Death-associated protein kinase 1 (DAPK1) is a serine/threonine kinase that plays a crucial role in cancer by regulating apoptosis through interactions with TP53. Aberrant expression of DAPK1 was shown in certain types of human cancer contributing to tumor progression and chemoresistance. This study aimed to investigate the role of DAPK1 in high-grade serous ovarian cancer (HGSOC) and to evaluate the therapeutic potential of restoring its kinase activity, including the use of truncated DAPK1 variants, to overcome chemoresistance and enhance tumor suppression. Methods: Gene expression analysis was performed on ovarian cancer tissues compared to benign controls to assess DAPK1 downregulation and its epigenetic regulation. Prognostic relevance was evaluated in a cohort of 1436 HGSOC patient samples. Functional restoration of DAPK1 was conducted in HGSOC cell lines and patient-derived primary tumor cells using vector-based expression or in vitro-transcribed (IVT) DAPK1 mRNA, including the application of truncated DAPK1 (ΔDAPK1) forms. To assess apoptosis, Caspase activation assays, 2D-colony formation assays, and cell survival assays were performed. To analyze the reactivation of DAPK1 downstream signaling, phosphorylation of p53 at Ser20 and the expression of p53 target proteins were examined. Chemosensitivity to Paclitaxel and Cisplatin was quantified by changes in IC₅₀ values. Results: DAPK1 expression was significantly downregulated in ovarian cancer compared to benign tissue, correlating with epigenetic silencing, and showed prognostic value in early-stage HGSOC. Restoration of DAPK1 activity, including ΔDAPK1 variants, led to phosphorylation of p53 Ser20, increased expression of p53 target proteins, and Caspase-dependent apoptosis. Reactivation of DAPK1 sensitized both established HGSOC cell lines and patient-derived ascites cells to Paclitaxel and Cisplatin. These effects occurred through both p53-dependent and p53-independent pathways, enabling robust tumor suppression even in p53-mutant contexts. Conclusions: Reactivation of DAPK1, particularly through truncated variants, represents a promising therapeutic strategy to overcome chemoresistance in HGSOC. The dual mechanisms of tumor suppression provide a strong rationale for developing DAPK1-based therapies to enhance the efficacy of standard chemotherapy, especially in patients with chemoresistant or p53-deficient tumors. Future work should focus on optimizing delivery approaches for DAPK1 variants and assessing their synergistic potential with emerging targeted treatments in clinical settings. Full article

Chromoanagenesis is a catastrophic genomic phenomenon involving sudden, extensive rearrangements within one or a few cell cycles. In osteosarcoma, the most prevalent malignant bone tumor in children and adolescents, these events dramatically alter the genomic landscape, frequently disrupting key tumor suppressor genes like TP53 and RB1, amplifying oncogene expression, and propelling tumor progression and evolution. This review elucidates how key chromoanagenic mechanisms, such as chromothripsis and chromoanasynthesis, arise from replication stress and impaired DNA repair pathways, ultimately contributing to genomic instability in osteosarcoma. Chromothripsis features prominently in osteosarcoma, occurring in up to 62% of tumor regions and driving intratumoral heterogeneity through persistent genomic crises. Next-generation sequencing, optical genome mapping, and emerging technologies like single-cell sequencing empower researchers to detect and characterize these complex structural variants, demonstrating how a single catastrophic event can profoundly influence osteosarcoma progression over time. While targeted therapies for osteosarcoma have proven elusive, innovative strategies harnessing comprehensive genomic profiling and patient-derived preclinical models hold promise for uncovering tumor-specific vulnerabilities tied to chromoanagenesis. Ultimately, unraveling how these rapid, large-scale rearrangements fuel osteosarcoma’s aggressive nature will not only refine disease classification and prognosis but also pave the way for novel therapeutic approaches to enhance patient outcomes. Full article

Alterations in aggressive-variant prostate cancer-associated tumor suppressor genes (AVPC-TSG: TP53, RB1, PTEN) are related with androgen insensitivity and aggressive disease. However, their prognostic and predictive role in metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. This single-center retrospective study assesses the value of AVPC-TSG alterations in refining prognosis and predicting the response to androgen receptor pathway inhibitors (ARPIs) in mHSPC. We included 158 patients with genomic tumor sequencing undergoing treatment for mHSPC between 2013 and 2023. We compared patients with AVPC-TSGalt tumors (≥1 alteration in TP53, RB1, or PTEN/PI3K/AKT pathway genes) to those with AVPC-TSGwt tumors (i.e., without alterations in AVPC-TSG). Cox analyses were performed for progression-free survival (PFS) and overall survival (OS). AVPC-TSGwt status was associated with improved PFS and OS in both univariate and multivariate (MV) analyses (MV PFS: HR 0.58, 95%CI: 0.38–0.89, p = 0.012; MV OS: HR 0.48, 95%CI: 0.26–0.91, p = 0.025). AVPC-TSGalt mHSPC patients seemed to derive no PFS benefit from ARPI addition (PFS: HR 1.13, 95%CI: 0.58–2.19, p = 0.721), while AVPC-TSGwt mHSPC patients did (PFS: HR 0.51, 95%CI: 0.28–0.93 p = 0.029). Integrating AVPC-TSG status with CHAARTED volume criteria, we identified three distinct subgroups: “good risk” (AVPC-TSGwt low volume), “intermediate risk” (either AVPC-TSGalt low volume or AVPC-TSGwt high volume), and “poor risk” (AVPC-TSGalt high volume) with median PFS of 46.8, 28.2, and 15.7 months, respectively. Only the “intermediate risk” subgroup seemed to derive PFS benefit from ARPI addition (HR 0.36, 95%CI: 0.19–0.70, p = 0.002). AVPC-TSG status assessment refines prognosis and may predict PFS benefits of ARPIs in mHSPC. AVPC-TSGalt mHSPC patients should be considered for clinical trials as they may not benefit from current standard approaches. Full article