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PubMed2025

Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis.

BACKGROUND: Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. METHODS: This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). RESULTS: Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10- 5). Additionally, the inhibition of FGFR1, FLT1, and MAP2K2 exhibited suggestive association with corresponding cardiovascular disease outcomes. Nevertheless, only VEGFA expression and stroke shared a causal variant (93.6%), whereas FGFR1, MAP2K2, and FLT1 did not share causal variants with corresponding cardiovascular diseases in the colocalization analysis. CONCLUSIONS: This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy.

Humans↗

PubMed2025

Relationship Between Cognitive Disorder and First-Line Targeted Therapy for Oncogene Driver-Positive Patients With Non-Small Cell Lung Cancer: Prospective Cohort Study.

BACKGROUND: Previous studies have found and confirmed a correlation between cognitive disorder and chemotherapy. As genetic testing becomes more routine in clinical practice, targeted therapies are increasingly gaining prominence. The relationship between targeted treatment and cognitive function is not yet clear. This study aimed to investigate the correlation between cognitive disorder and targeted treatment by evaluating the changes in cognitive function before and after targeted therapy. OBJECTIVE: This study aims to explore whether targeted therapy affects cognitive function in patients with advanced lung cancer and to explore the association between cognitive function, the inflammatory biomarker C-reactive protein, and psychological stress. METHODS: From the screened cohort of 150 patients with advanced non-small cell lung cancer (NSCLC) with gene mutations, 87 (58%) were rigorously selected for the study. The evaluation instruments used were the Mini-Mental State Examination scale, the Distress Thermometer, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 for assessing quality of life. RESULTS: A significantly lower progression-free survival (PFS) was observed in the group of patients surviving advanced NSCLC with cognitive disorder under targeted therapy in contrast to survivors in the group with no cognitive disorder (hazard ratio=0.347, 95% CI 0.209-0.578; P<.001). Furthermore, the objective response rate and disease control rate for the group with cognitive disorder were noted to be 37.8% and 86.7%, respectively, contrastingly lower than those in the group with no cognitive disorder, recorded at 78.6% and 97.6%, respectively. Significant variances were also noted in the Mini-Mental State Examination scores between patients with and without cognitive disorder both before and after targeted therapy (P<.001 in both cases), with a decreasing trend observed in both groups after targeted therapy. Noteworthy differences were found in quality of life scores both before and after targeted therapy (P<.001 in both cases). In addition, notable disparities were apparent in C-reactive protein levels among the 2 groups before and after treatment (P=.03 and P=.048 for each time point, respectively), with an upward trend observed in both groups after targeted therapy. The multivariate Cox regression analysis demonstrated that cognitive function is an independent risk factor for PFS in patients with NSCLC receiving targeted therapy. CONCLUSIONS: Cognitive disorder may lead to lower quality of life scores and shorter PFS in patients undergoing targeted therapy. Early screening and intervention for such patients could effectively improve clinical outcomes and quality of life.

Humans↗

PubMed2026

Pancreatic Cancer: Translating Tumor Biology into Actionability.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers and has a very poor prognosis. Ten to 15% are staged as resectable at diagnosis, and 5% to 15% downstaged with therapy to where surgery is feasible. Chemotherapy is a mainstay for all stages of PDAC. Targeted therapies are available for patients with select but expanding actionable genomic alterations. The tumor microenvironment provides a dense stroma with an immunosuppressive milieu that contributes to inherent treatment resistance of PDAC. Herein, we review current management of PDAC with a focus on emerging treatment paradigms, including targeted and immunomodulatory agents. SIGNIFICANCE: PDAC is a complex disease with unique genomic, immunologic, and clinical features. Recent developments in understanding of the pathobiology of this disease are translating into targeted and immunomodulatory therapies that will alter treatment paradigms and improve outcomes for this recalcitrant malignancy.

Humans↗

PubMed2026

KRAS Expression Complements Genomic Profiling in Identifying Therapeutic Vulnerability in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) remains a major therapeutic challenge. Although alterations in the RAS pathway occur in over 50% of tumors, only a limited proportion are clinically actionable. We investigated whether KRAS expression complements genomic profiling for patient stratification and therapeutic vulnerability in GC. METHODS: Comprehensive genomic profiling was performed in 19 Taiwanese GC patients and compared with TCGA-STAD data (n = 434). KRAS mRNA expression and overall survival were evaluated by meta-analysis of 13 independent cohorts (n = 2,521). Protein-level validation was performed by immunohistochemistry in an independent cohort (n = 121). Functional KRAS dependency and response to combined MEK/SHP2 inhibition were assessed in eight GC cell lines. RESULTS: KRAS amplification was entirely contained within the KRAS-high population, whereas most KRAS-high tumors lacked detectable amplification. High KRAS expression was associated with poorer overall survival (HR 1.23, p = 0.001) and remained an independent prognostic factor after multivariable adjustment (adjusted HR 1.24, p = 0.003). Protein-level analysis showed a concordant trend. KRAS expression correlated strongly with functional dependency (R2 = 0.88, p = 0.005), was enriched in MSI and CIN subtypes, and identified cell lines with enhanced sensitivity to combined MEK/SHP2 inhibition. CONCLUSIONS: KRAS expression complements genomic profiling by identifying biologically relevant KRAS-dependent GCs beyond mutation or amplification alone. Integrating expression-based stratification with genomic profiling may improve patient selection for RAS pathway-directed combination therapies.

Biomarker↗

PubMed2025

[First results of comprehensive genomic studies on solid tumours in National Institute of Oncology].

AIMS: The Molecular Pathology Laboratory of the National Institute of Oncology has been performing comprehensive genomic studies (500-gene panel) since 2021. This paper summarizes our results obtained between 2022 and 2024, focusing on clinical requests, the histological type of cases studied and the potential therapeutic benefit of identified variants. METHODS: Comprehensive genomic profiling was performed using next generation sequencing on an Ion S5 Plus system (Thermo Fisher Scientific) with Oncomine Comprehensive Assay Plus kit. DNA and RNA were extracted from formalin- fixed, paraffin-embedded samples. RESULTS: 402 analyses were performed. We identified mutations with therapeutic significance in 37.3% (150/402) of cases, including 26.4% (106/402) of cases with on label therapies. The most frequently investigated cases were soft tissue sarcomas and gynaecological tumours. CONCLUSIONS: Genetic alterations with therapeutic relevance primarily include high TMB and high GIS. Previously unknown mutations suitable for targeted therapy were rarely identified, as almost all cases had previously undergone small targeted panel testing.

Humans↗

PubMed2026

Human Epidermal Growth Factor Receptor-2 positive metastatic salivary duct carcinoma with remarkable response to targeted therapy: a case report and therapeutic implications.

Salivary duct carcinoma (SDC) is a rare and highly aggressive malignancy that frequently overexpresses Human Epidermal Growth Factor Receptor 2 (HER2). Despite the increasing recognition of HER2-targeted strategies, evidence remains limited and largely derived from small trials and case series. We report the case of a middle-aged man with HER2-positive metastatic SDC who achieved near-complete pathologic and radiological response to trastuzumab and docetaxel, enabling surgical resection for locoregional control. This case highlights the role of anti-HER2 therapy as a first-line strategy in SDC and underscores the importance of individualized management plans integrating systemic treatment and locoregional measures.

Humans↗

PubMed2026

Next-Generation Sequencing Completion and Timeliness Using a Reflex Testing Protocol for Patients with Stage II to IV Nonsquamous Non-Small Cell Lung Cancer.

BACKGROUND: Next-generation Sequencing (NGS) is critical for providing treatment recommendations across multiple stages of non-small cell lung cancer (NSCLC). However, a substantial proportion of patients do not undergo testing. This study evaluated the completion rates and timeliness of NGS in patients with stage II to IV NSCLC at a single academic institution with a reflex NGS testing protocol. METHODS: Patients with stage II to IV nonsquamous NSCLC (ns-NSCLC) diagnosed between 2015 and 2022 were identified retrospectively. A reflex, tissue-based testing protocol was initiated in 2015 using in-house NGS. Pyrosequencing was performed if NGS failed. RESULTS: 501 patients were included: 75 (15.0%) with stage II, 82 (16.4%) with stage III, and 344 (68.6%) with stage IV ns-NSCLC. Tissue NGS was completed in 380 (75.8%) patients and 465 (92.8%) completed some tissue-based genomic testing when including pyrosequencing. Median time from biopsy to NGS was 17.0 days (range, 6-61 days). 61.0% of patients had NGS results prior to a first treatment of any type and 88.4% had tissue NGS results prior to systemic therapy. Among stage IV patients with completed NGS, median overall survival was 2.27 years for patients with NGS results prior to first treatment compared to 1.08 years for patients without NGS results prior to treatment initiation (P = .04). CONCLUSIONS: Implementation of an in-house, reflex NGS testing protocol enabled rapid genomic profiling in a high proportion of patients with stage II to IV ns-NSCLC. NGS completion prior to receiving first-line therapy was associated with improved survival compared to completion after first line treatment in stage IV patients.

Humans↗

PubMed2026

Emerging Strategies Targeting the PI3K/AKT/mTOR Pathway in HR+/HER2- Advanced Breast Cancer.

Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 70% of breast cancer cases. Despite recent advances with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), resistance inevitably develops, often driven by activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. Genetic alterations such as PIK3CA mutations (present in ~ 45% of HR+/HER2- tumors), AKT1 mutations, and PTEN loss contribute to endocrine resistance and poor outcomes. This review summarizes emerging strategies targeting this pathway to overcome resistance in advanced disease. Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population. Next-generation agents, including mutant-selective PI3Kα inhibitors and bi-steric mTOR complex 1 inhibitors, are under active investigation. Optimal sequencing of these agents alongside endocrine therapy and CDK4/6i options remain a critical question, as does integration of genomic testing to guide therapy. Future directions include rational combination strategies, improved biomarker-driven selection, and novel modalities such as proteolysis-targeting chimeras (PROTACs). Collectively, these advances aim to enhance durability of response, minimize toxicity, and improve survival in HR+/HER2- metastatic breast cancer.

Humans↗

PubMed2025

Imidazole propionate is a driver and therapeutic target in atherosclerosis.

Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors1. However, individuals at risk for early vascular disease often remain unidentified2. Recent research has identified new molecules in the pathophysiology of atherosclerosis3, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy. Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation. Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP-I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP-I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.

Atherosclerosis↗

PubMed2026

Decoding context-dependent sirtuin pharmacology in cancer: Metabolic-epigenetic switches and precision therapeutic targeting.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Humans↗

PubMed2026

Availability and public reimbursement of early breast cancer care across European expert centres: a PORTRAIT from an EUSOMA initiative.

BACKGROUND: Cross-country disparities in access to guideline-recommended early breast cancer care persist across Europe. PORTRAIT is a clinician-reported, cross-sectional access study mapping availability and state reimbursement of key services across the early breast cancer pathway. METHODS: A 49-item survey covering diagnostics, pathology and genomics, systemic therapy, surgery, radiotherapy, and supportive care was emailed from June to September 2024 to multidisciplinary teams at one expert breast centre in 42 European countries. Respondents provided a consensus perspective on service availability and reimbursement. Descriptive proportions with full, partial, or no access were calculated. RESULTS: Thirty-nine countries responded (93%). Core diagnostics were widely available, but gaps persisted: MRI-guided biopsy was absent in 29% of countries and vacuum-assisted biopsy was fully reimbursed in 66%. Genomic assays were unavailable in 14% and not fully reimbursed in 35%. Public funding gaps were reported for PARP inhibitors (33%) and CDK4/6 inhibitors (26%). Immediate implant-based reconstruction and biological meshes lacked reimbursement in 21% and 33%, respectively. Despite broad availability of hypofractionated radiotherapy, 38% of countries still used per-fraction reimbursement. Psycho-oncology was limited in 35%, fertility preservation in 46%, and patient-reported outcome measures absent in 43%. CONCLUSION: Basic services are nearly universal, but gaps persist in advanced imaging, molecular testing, targeted therapies, radiotherapy reimbursement, reconstructive/oncoplastic surgery, and survivorship care. PORTRAIT identifies practical targets for policy audit, reimbursement alignment, and resource stewardship. Findings reflect clinician perspectives from expert centres, potentially representing best specialist care rather than average national care, and are not population-representative estimates or direct measures of patient outcomes.

Humans↗

PubMed2025

Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting.

Across the landscape of oncogene-addicted non-small-cell lung cancer (NSCLC), various tyrosine kinase inhibitors (TKIs) have been introduced in the last twenty years. During the 2024 Annual ESMO meeting new therapeutic options were presented for EGFR exon 20 insertion mutation, ALK fusion and ROS1 fusion positive advanced stage NSCLC. For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI. The vast majority of these patients also received platinum-doublet chemotherapy. For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib. The median number of prior anticancer therapies was 3. Intracranial responses were seen in lorlatinib naïve- and lorlatinib pretreated patients and toxicity was manageable. In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib. Iruplinalkib showed a superior median PFS (36.8 versus 14.55 months for crizotinib), but no difference in 36-month overall survival (OS) rate. Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in patients that were pretreated with crizotinib and an ORR of 38% in patients pretreated with repotrectinib. In this review, we will discuss the relevant study results presented at ESMO 2024 for these three genomic drivers and hypothesize on their respective place in the sequence of treatment options.

Humans↗

PubMed2026

Expression patterns of potential targets for antibody-directed therapy in metastatic castration-resistant prostate cancer patients.

INTRODUCTION: Survival in metastatic castration-resistant prostate cancer (mCRPC) patients remains limited and treatment is complicated by tumor heterogeneity. As antibody-based therapeutics emerge, identifying actionable antigen targets and patient subgroups most likely to benefit is essential. MATERIALS & METHODS: Gene expression of 62 antibody-targetable proteins was analyzed in 296 mCRPC biopsies. These genes encode proteins targeted by approved or investigational antibody-based cancer therapeutics. Associations between target expression with genomic classifications and transcriptomic subtypes were evaluated. Target expression was also assessed in tumors with low expression of established mCRPC targets. Subgroup-specific targets were validated in an independent cohort and single-cell transcriptomics. RESULTS: Established targets KLK2, FOLH1 (PSMA) and STEAP1 showed the highest median expression across the cohort. Target expression did not correlate with genomic classifications, including homologous recombination deficiency, microsatellite instability, CDK12, TP53, PTEN or AR alterations Target expression did associate with transcriptomic subtypes: CRPC-AR (driven by androgen receptor-signaling) and CRPC-SCL (stem cell-like features, AP-1/YAP/TAZ-driven), displayed the highest expression of multiple targets, including KLK2, FOLH1, and SLC44A4. CRPC-NE (neuroendocrine phenotype) showed heterogeneous expression, with high CD46 expression, whereas CRPC-WNT (Wnt-signaling driven) generally showed low target expression. Notably, CD46 was highly expressed in tumors with low KLK2, FOLH1, and STEAP1 expression, a subgroup associated with poor prognosis. CONCLUSIONS: Although several antibody targets showed broad expression in mCRPC-tumors, expression varied by transcriptomic subtype. Subgroups such as CRPC-WNT expressed fewer targets, suggesting the need for alternative therapeutic strategies. CD46 emerged as a promising target, with wide expression across multiple subtypes, including clinically challenging CRPC-NE and mCRPC tumors lacking expression of established targets.

Humans↗

PubMed2026

MET Exon 14 Skipping Mutation in NSCLC: From Genomic Discovery to Biomarker-Guided Therapeutic Innovation.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and the MET exon 14 skipping mutation is a key oncogenic driver, which promotes tumor progression and provides a new direction for precision therapy. METHODS: A systematic search of English-language literature and clinical trial data related to the MET exon 14 skipping mutation from 2020-2025 was performed to summarize the role of the mutation and therapeutic advances. RESULTS: DNA-based next-generation sequencing (NGS), RNA-based NGS, and RT-qPCR were employed as the main detection methods. Preclinical models confirmed that mutations promote tumor progression by activating the RAS/MAPK pathway. Clinical trials have reported objective remission rates (ORR) of 46-68% for first-line treatment with MET inhibitors in NSCLC patients harboring MET exon 14 skipping mutations. DISCUSSION: MET exon 14 skipping mutation as a therapeutic target for NSCLC has made significant progress, and MET inhibitors are more advantageous than chemotherapy and immunotherapy, and have been recommended by national and international guidelines as a first-line treatment option. Additionally, NGS technology has the potential to dynamically monitor tumor evolution and drugresistant mutations, thereby helping to realize precision medicine. CONCLUSION: The MET exon 14 skipping mutation is an important target for the precision treatment of NSCLC, and MET-TKIs have remarkable efficacy but a prominent problem with drug resistance. The construction of a precision medicine system encompassing diagnosis, treatment, and drug resistance management through multi-omics research, technological innovation, and international collaboration is a key direction for improving prognosis.

Humans↗

PubMed2026

Associations of neighborhood deprivation with breast cancer tumor genomics, targeted treatment use, and survival.

PURPOSE: Neighborhood environments appear to influence breast cancer biology and outcomes. This study evaluated somatic, treatment, and outcome differences by Area Deprivation Index in patients with metastatic breast cancer. METHODS: Retrospective, population-based cohort study using clinical and genomic data gathered between 2015 and 2024 at four academic institutions in the United States. The outcomes were differences in circulating tumor DNA mutation profiles, PI3K inhibitor use, and survival between patients with metastatic breast cancer living in high deprivation (Area Deprivation Index ≥ 60 by national rank) and low deprivation (< 60) neighborhoods. RESULTS: Among 1127 patients with metastatic breast cancer, 335 (29.7%) lived in high deprivation areas. These patients were more likely to have TP53 mutations (Odds ratio 1.49, 95% Confidence Interval 1.07-2.08, P = 0.018). Among hormone receptor-positive, HER2-negative patients eligible for PI3K inhibitors, those from high deprivation areas were less likely to receive them (17.4% vs. 36.7%, p = 0.02). Median survival from the time of circulating tumor DNA testing was significantly shorter in the high deprivation group (24 months versus 28 months, p = 0.04) and for Black patients in the high deprivation group versus Black patients in low deprivation group and all White patients (15 months versus 25-28 months, p = 0.02). CONCLUSIONS: We found that patients with metastatic breast cancer living in high deprivation neighborhoods were more likely to have TP53 mutations, an indicator of aggressive disease biology, less likely to receive PI3K inhibitors, and had shorter overall survival compared to patients living in low deprivation neighborhoods by Area Deprivation Index.

Humans↗

PubMed2025

Annexin A2 binds the 3'-UTR of H2AX mRNA and regulates histone-H2AX-derived hypoxia-inducible factor 1-alpha activation.

Annexin A2 (Anxa2), a multifunctional protein with RNA-binding capabilities, is frequently overexpressed in various tumors, and its expression is highly correlated with malignant progression. In this study, we demonstrate for the first time that Anxa2 was co-expressed with glycolytic genes, suggesting its potential role as a regulator of glycolysis. RNA-protein interaction assay revealed that Anxa2 interacted with 3'-UTR of H2AX mRNA and protected it from miRNA-mediated degradation. Up-regulated Histone-H2AX enhances the expression of glycolytic genes including GLUT1, HK2, PGK1, ENO1, PKM2, GAPDH and LDHA via stabilizing hypoxia-inducible factor 1-alpha (HIF1α), thereby accelerating lactic acid production and secretion. (20S) G-Rh2, a natural compound targeting Anxa2, significantly interfered the Anxa2-H2AX mRNA interaction, and inhibited subsequent glycolysis progression. We propose that Anxa2 acts as a novel regulator in glycolysis via enhancing H2AX expression, and (20S) G-Rh2 may exert its anti-cancer activity by targeting Anxa2-H2AX-HIF1α-glycolysis axis in human hepatoma HepG2 cells.

Humans↗

PubMed2026

Insights into FACT in Cancers with Targeted Therapeutic Implications.

Facilitates chromatin transcription (FACT) is an evolutionarily conserved chromatin remodeling factor. It controls chromatin states in an ATP-independent manner via the regulation of chromatin assembly and disassembly. Through such regulation, FACT is involved in controlling transcription and other DNA-transacting processes such as replication and repair. However, it is surprisingly found to be upregulated in various cancers, and upregulated FACT induces oncogenesis and supports cancer cell survival, aggressiveness and metastasis, thus implying it to be a prognostic marker for cancer with an attractive targeted therapeutic potential. Here, we describe the involvement of FACT in various cancers with mechanistic insights and potential targeted therapeutic implications.

Humans↗

PubMed2019

Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance.

Obesity is an increasing pathophysiological problem in developed societies. Despite all major progress in understanding molecular mechanisms of obesity, currently available anti-obesity drugs have shown limited efficacy with severe side effects. CRISPR interference (CRISPRi) mechanism based on catalytically dead Cas9 (dCas9) and single guide RNA (sgRNA) was combined with a targeted nonviral gene delivery system to treat obesity and obesity-induced type 2 diabetes. A fusion peptide targeting a vascular and cellular marker of adipose tissue, prohibitin, was developed by conjugation of adipocyte targeting sequence (CKGGRAKDC) to 9-mer arginine (ATS-9R). (dCas9/sgFabp4) + ATS-9R oligoplexes showed effective condensation and selective delivery into mature adipocytes. Targeted delivery of the CRISPRi system against Fabp4 to white adipocytes by ATS-9R induced effective silencing of Fabp4, resulting in reduction of body weight and inflammation and restoration of hepatic steatosis in obese mice. This RNA-guided DNA recognition platform provides a simple and safe approach to regress and treat obesity and obesity-induced metabolic syndromes.

3T3 Cells↗