Search Results (3,131)

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are usually driven by activating mutations in KIT or PDGFRA. Although these alterations define the core molecular biology of GISTs and guide targeted therapy, they do not fully explain the variability observed in tumor behavior, recurrence risk, or response to tyrosine kinase inhibitors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been increasingly studied as regulators of gene expression in GISTs. Recent evidence suggests that these molecules may influence KIT-centered signaling, autophagy, apoptosis, invasion, angiogenesis, and drug resistance. However, the strength of evidence differs considerably across individual ncRNAs, ranging from bioinformatic associations to functional validation in cell lines and in vivo models. This review summarizes current knowledge on ncRNA-mediated regulation in GIST biology, with emphasis on tumor progression, therapeutic resistance, and possible clinical relevance. Rather than treating ncRNAs as isolated biomarkers, they function as part of broader regulatory networks that interact with oncogenic signaling and epigenetic mechanisms. Although several ncRNAs appear promising as prognostic or predictive candidates, further validation in independent clinical cohorts is required before their integration into routine risk stratification or treatment decision-making. Full article

Background/Objectives: Oligometastatic GIST, defined in this study as five or fewer metastatic lesions confined to a single organ, represents a distinct subset with a lower metastatic burden than widely metastatic disease and may have different prognostic and therapeutic considerations. Methods: We reviewed biopsy-proven oligometastatic GIST diagnosed between August 1998 and June 2025 from a prospectively maintained institutional database, collecting genomic, metastatic, treatment, ethnicity, and survival data. Overall survival (OS), calculated from diagnosis of oligometastatic disease, was estimated by Kaplan–Meier analysis and compared using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Results: Of 525 subjects with GIST in our database, 96 (18.3%) had oligometastatic GIST (median age: 54 years; median OS from diagnosis of oligometastatic disease: 9.77 years). Most tested tumors were KIT-positive (91.6%), predominantly harboring KIT exon 11 alterations (69.5%). The most common metastatic sites were the liver (n = 44) and peritoneum (n = 37). Overall, 58 patients underwent surgery, including 55 cytoreductive procedures and 3 emergent operations for bleeding or obstruction. Among the cytoreductive procedures, indications included multifocal disease after tyrosine kinase inhibitor (TKI) response (n = 21), unifocal disease after TKI response (n = 18), unifocal progression on TKI (n = 13), and equivocal or undocumented TKI response (n = 3). Overall survival did not differ by liver versus peritoneal metastases (HR: 1.27; 95% CI, 0.59–2.70; p = 0.540) or Hispanic versus non-Hispanic ethnicity (HR: 0.81; 95% CI, 0.34–1.90; p = 0.624). Cytoreductive surgery combined with systemic therapy was associated with longer overall survival than systemic therapy alone (10.8 vs. 7.4 years; HR: 0.44; 95% CI, 0.22–0.89; p = 0.019). Conclusions: In this retrospective cohort, cytoreductive surgery combined with systemic therapy was associated with longer overall survival than systemic therapy alone. Full article

Sorafenib is widely used to treat metastatic renal cell carcinoma (RCC); however, the acquired drug resistance limits its efficacy and application in clinical practice. The receptor tyrosine kinases c-Met and AXL play important roles in cancer progression and are involved in tyrosine kinase inhibitor-induced drug resistance in cancers, but whether these two receptors also contribute to sorafenib-induced drug resistance in RCC is unclear. In this study, we evaluated our synthesized compound 1D228, a TKI derived from Tepotinib, in sorafenib-resistant RCC models, which demonstrated further inhibition in sorafenib-resistant RCC cells, and induced 25% more reduction in resistant RCC tumor size by 1D228 combined with sorafenib compared with sorafenib monotherapy in animal models. Mechanistically, resistant RCC exhibited elevated phosphorylation of c-Met and AXL, which was effectively suppressed by 1D228. These findings indicated that compound 1D228 sensitized the sorafenib resistance of RCC by dual targeting the c-Met and AXL signaling pathways. This study suggests that 1D228 may represent a promising preclinical therapeutic strategy for RCC patients with sorafenib resistance mediated by c-Met and AXL activation. Full article

Indolo[2,3-b]quinoxalines, along with their N-substituted derivatives, exhibit pronounced anticancer activity, although the mechanisms of their biological action may vary. Herein, a panel of sixty-five 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives comprising eight series with distinct amine moieties connected to the tetracyclic indoloquinoxaline core via a dimethylene linker was evaluated as drug-like candidates for kinase binding and cytotoxic activity. The ADME (Absorption, Distribution, Metabolism, and Excretion) properties of the compounds included in this set were preliminarily determined using the SwissADME tool. Analysis revealed that the library of quinoxaline derivatives largely complies with the drug-likeness rule for kinase-targeted compounds. As part of the biological screening, the compounds were initially tested on two cell lines MonoMac-6 and THP-1 (both derived from patients with acute monocytic leukemia) using sunitinib, a known antitumor agent acting as a multi-target receptor tyrosine kinase inhibitor, as a reference compound. Compound 3g, which demonstrated the highest activity in the cytotoxicity analysis (IC₅₀ = 1.9 and 3.5 μM for the MonoMac-6 and THP-1 cell lines, respectively), was screened using the Eurofins DiscoverX scanEDGE panel, comprising 97 distinct kinases representing all known kinase families. Subsequently, the compound was tested using the Eurofins DiscoverX scanTK™ panel, covering 135 distinct receptor and non-receptor tyrosine kinases. Based on initial screening results, compound 3g exhibits relatively high binding activity against fourteen tyrosine kinases, including TYK2, ZAP70, eight mutant forms of ABL1, two mutant forms of FLT3, and one mutant form of ALK, and demonstrates relatively high binding selectivity with respect to non-mutant tyrosine kinases (S-score: 0.024). Secondary screening of nine selected analogs of compound 3g led to the identification of compound 3h, which demonstrates relatively high binding affinity for FLT3 (D835V) (K_d = 0.41 μM). Molecular modeling suggested modes of binding interaction of the compounds 3h and 3g in the FLT3 (D835V) catalytic site. Our results demonstrate that 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives could be potential candidates for developing anticancer drugs. Full article

Primary bone sarcomas are rare, heterogeneous malignancies with limited therapeutic options, particularly in metastatic disease where outcomes remain poor. This study synthesizes current literature to evaluate emerging therapeutic strategies and biological determinants of response across osteosarcoma, Ewing sarcoma, and chondrosarcoma, as presented at the ESMO Annual Meeting, 2025. Key approaches reviewed include VEGFR-targeted tyrosine kinase inhibitors (TKIs), DNA damage response (DDR) inhibition, MYC targeting, immune checkpoint inhibitors (ICIs), and surfaceome-directed therapies such as antibody–drug conjugates (ADCs) and chimeric antigen receptor T cell therapy. Across studies, TKIs demonstrated short lasting activity as monotherapy but improved outcomes in some of the studies when combined with ICIs or chemotherapy, reflecting their role in remodeling the tumor microenvironment (TME); importantly, controlled studies with TKI and chemotherapy upfront are ongoing. DDR- and MYC-targeted therapies have shown strong preclinical rationale but limited clinical efficacy, highlighting challenges in translation. Immune-based therapies exhibited variable responses, with dedifferentiated chondrosarcoma (DDCS) emerging as a responsive histotype. Surfaceome-targeting strategies, particularly ADCs, demonstrated promising early clinical activity. Overall, bone sarcoma rarity, tumor heterogeneity, immunosuppressive TME, and lack of predictive factors challenge drug discovery for bone sarcoma patients. These findings underscore the importance of combination strategies and biomarker-driven patient selection and suggest that continued integration of targeted and immunotherapeutic approaches will be critical to improving outcomes in bone sarcoma. Full article

Bruton tyrosine kinase inhibitors have transformed the management of chronic lymphocytic leukemia and other B-cell malignancies, but their clinical use is increasingly influenced by cardiovascular safety. In contemporary practice, patients receiving these therapies are typically older and characterized by a high burden of comorbidities, including cardiovascular disease, metabolic disorders, and renal impairment. In this setting, cardiovascular complications should not be interpreted as isolated adverse events, but rather as clinical expressions of underlying patient vulnerability and frailty. Atrial fibrillation and arterial hypertension represent the most frequent complications, while heart failure, ventricular arrhythmias, and bleeding, although less common, may carry significant prognostic implications. Importantly, these events often arise from the interaction between drug exposure and pre-existing comorbidities, and may lead to treatment interruption, dose reduction, or discontinuation, ultimately compromising the long-term benefit of otherwise highly effective therapies. This review provides a comprehensive overview of the clinical burden, mechanisms, and management of cardiovascular complications associated with these agents, and proposes a practical, patient-centered framework to guide clinical decision-making. A structured approach based on risk assessment, early detection, and proactive management is essential to prevent complications, optimize treatment continuity, and preserve the long-term benefit of therapy in a complex and vulnerable population. Full article

Background and Objectives: During the 2016–2022 period, tyrosine kinase inhibitor (TKI) monotherapy was the standard first-line option at our center before combination protocols became available. This study evaluates patients experiencing initial TKI failure who subsequently received second- or later-line nivolumab. Because clinical practice lacks low-cost, accessible tools to prognosticate outcomes in this setting, we evaluated whether baseline psoas muscle index (PMI), early on-treatment C-reactive protein (CRP) kinetics, and a specific panel of blood-derived inflammatory/nutritional ratios offer reliable prognostic value. Materials and methods: We retrospectively reviewed data from 49 consecutive mRCC patients who progressed on a TKI and received second- or later-line nivolumab monotherapy. Primary endpoints were overall survival (OS; N = 49) and time-to-treatment failure (TTF; N = 48). We utilized Kaplan–Meier and Cox regression models for analysis. Benjamini–Hochberg false discovery rate (FDR) correction (q < 0.05) controlled false positive inflation across two separate testing frameworks: seven log-rank assessments for TTF and the core Cox models. Adjusted models accounted for clinical covariates including International Metastatic RCC Database Consortium (IMDC) risk category, Eastern Cooperative Oncology Group performance status (ECOG PS), and de novo metastatic presentation. We calculated the intraclass correlation coefficient (ICC) to evaluate measurement reproducibility. Results: Median follow-up reached 48.4 months (reverse Kaplan–Meier; maximum: 87.8 months), with a cohort-wide median OS of 13.9 months (IQR: 5.8–36.2). A low baseline C-reactive protein-to-albumin ratio (CAR) mapped to a distinct survival benefit, showing a median OS of 32.6 months versus 5.8 months in the high-CAR group (log-rank p < 0.001; BH q = 0.003). In adjusted multivariable Cox hazards modeling, both CAR (HR: 1.029; p = 0.002) and the prognostic nutritional index (PNI; HR: 0.893; p < 0.001) maintained independent prognostic significance. When evaluating the 43 patients with complete 3-month CRP records, we found a significantly higher objective response rate (ORR) in those at or below the cohort-median ratio threshold of 1.16 compared to patients above it (54.5% vs. 23.8%; p = 0.039). The overall ITT population registered an ORR of 36.7% (18/49). Conclusions: Low pretreatment CAR and elevated PNI identify mRCC patients showing improved survival profiles in this post-TKI nivolumab subgroup. Additionally, an elevated 3-month CRP ratio correlates with compromised objective response rates and a trend toward shorter TTF, though the TTF endpoint did not clear strict FDR parameters (BH q = 0.098). These retrospective, single-center data serve strictly for signal generation and require independent prospective multi-institutional confirmation before translating to oncology practice. Full article

Background/Objectives: Quiescent leukemia stem cells (LSCs) are self-renewing, pluripotent cells that present a major obstacle to the successful curative treatment of chronic myeloid leukemia (CML). LSCs function independently of BCR::ABL1 signaling and persist following tyrosine kinase inhibitor treatment. The mechanisms enabling LSC survival are a central focus of current CML research. This review details the complex relationship between signaling pathways and discusses recent advancements in energy metabolism research within the pathogenesis of CML. Discussion: Energy metabolism is critical to the biology of CML LSCs. These cells depend on oxidative phosphorylation (OXPHOS) and mitochondrial homeostasis, utilizing fatty acid oxidation as their primary ATP source. Research highlights significant alterations in signaling networks, marked by a dynamic interplay among dominant pathways within the CML clone. While TGF-β-FOXO signaling maintains the self-renewal capacity of quiescent LSCs, proliferating mature CML cells rely heavily on glycolysis and the PI3K/Akt pathway. Furthermore, unique metabolic traits of LSCs underscore the impact of leukemic cell–microenvironment interactions in fostering a permissive niche. Conclusions: Fatty acid oxidation is critical to the survival and self-renewal of CML LSCs. This adaptation of mitochondrial function is closely linked to signaling alterations and entails an adjustment of mitochondrial respiration alongside stimulated OXPHOS. Emerging research unveils many potential targets within metabolic signaling that can be exploited to overcome these survival mechanisms, highlighting the disruption of mitochondrial energy support as a promising strategy to selectively eradicate CML LSCs. Full article

Background: Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLN-FGFR1), also known as 8p11 myeloproliferative syndrome, are rare and aggressive hematologic malignancies arising from pluripotent stem cells. The FGFR1::ZMYM2 fusion resulting from t(8;13)(p11.2;q12) characteristically co presents as T-lymphoblastic lymphoma in lymph nodes alongside a myeloproliferative neoplasm in the bone marrow. The disease is resistant to tyrosine kinase inhibitors and conventional chemotherapy, and carries a median survival of less than 12 months without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Case Presentation: We report a 23-year-old female who presented with progressive cervical lymphadenopathy and hyperleukocytosis (WBC 186.6 K/μL). Excisional lymph node biopsy demonstrated T-cell acute lymphoblastic lymphoma (T-ALL) with eosinophilic infiltration; immunohistochemistry confirmed lymphoblasts positive for CD1a, CD2, CD3, CD4, CD5, CD7, CD8, and TdT. Concurrent bone marrow biopsy showed a myeloproliferative neoplasm without excess blasts. Chromosomal analysis confirmed t(8;13)(p11.2;q12) with FGFR1::ZMYM2 rearrangement, and NGS identified a concurrent CSF3R variant (Q741*). She received induction chemotherapy per the PEDS AALL1231 protocol (Arm A) followed by consolidation, with a course complicated by hyperleukocytosis, venous thromboembolism, E. coli bacteremia, and severe mucositis requiring PICU admission. Despite initial response, the disease progressed to acute myeloid leukemia (AML) with acquisition of a PTEN variant; the patient was offered but did not complete allo-HSCT and died of refractory AML approximately 10 months after diagnosis. Conclusions: This case highlights the aggressive clinical course and diagnostic challenges of MLN-FGFR1, a rare stem cell-derived myeloid/lymphoid neoplasm. To our knowledge, this appears to be the first reported case documenting sequential CSF3R and PTEN variant acquisition with complete follow-up through fatal AML transformation, and the first to describe treatment with a pediatric ALL induction protocol (PEDS AALL1231) in this setting. The characteristic histomorphologic pattern of eosinophil-rich T-ALL in lymph nodes with concurrent myeloproliferative neoplasm in bone marrow should prompt immediate molecular workup. Allo-HSCT must be pursued urgently at diagnosis, as complications rapidly narrow the transplant window and the disease is uniformly fatal without it. Full article

Background: Increasing resistance against protein kinase inhibitors used in cancer therapies enforces the search for novel target structures to be addressed with favourable small-molecule inhibitors. One of these novel target structures is the tyrosine kinase Brk that is known to play a prominent role in breast cancer progression. Moreover, Brk overexpression in various kinds of cancer is associated with poor outcomes, making Brk an interesting target structure for potential treatment. So far, no class of promising Brk inhibitors has been identified. Methods: We synthesized novel functionalized pyrrolopyridines in one- and two-step reactions under substitution of the molecular scaffold and the 4-aniline residue, respectively. They were evaluated as inhibitors of Brk and HER2 in a radiolabelled enzyme assay. Results: The most favourable substituents for Brk inhibitory activity at the aniline residues were 3-hydroxy functions combined with either bromo or nitro substituents at the molecular scaffold. Those compounds, as well as bromo- and nitro-substituted compounds, also showed the best HER2 inhibitor activities. Conclusions: Novel pyrrolopyridines were discovered to be a promising class of nanomolar Brk inhibitor with additional HER2 activities to further strengthen Brk inhibitory activity in prospective anticancer therapies. Thus, the first class of Brk inhibitors could be identified. Full article

Keratoconus (KC) is a degenerative corneal disease, characterized by stromal thinning and abnormal ECM remodeling, leading to fibrosis. Corneal fibrosis is a leading cause of visual impairment. Corneal stromal keratocytes differentiate into myofibroblasts, which alters extracellular matrix (ECM) protein deposition. Nintedanib (NIN) is an antifibrotic FDA-approved tyrosine kinase inhibitor, but its function in the cornea is largely unknown. This study examined the impact of NIN within the human corneal stromal microenvironment. Healthy corneal stromal fibroblasts (HCFs) and KC fibroblasts (HKCs) in 2D and 3D in vitro cultures were treated with 1 μM or 2.5 μM NIN. Cell types were evaluated in 2D cultures for metabolic activity, viability, and migration. Protein expression of alpha-smooth muscle actin (α-SMA), collagens (COLs) 1, 3, and 5, cellular fibronectin containing extra domain A (EDA-FN), and thrombospondin-1 (TSP-1) were evaluated in 3D cultures. NIN reduced metabolic activity in HKCs without affecting cell viability. NIN reduced cell migration, downregulated COL3, COL5, EDA-FN, and TSP-1 expression in HCFs and HKCs. COL1 was upregulated in HCFs, whereas α-SMA was upregulated in HKCs. Overall, these findings demonstrate that NIN modulates corneal stromal cell migration and fibrotic marker expression, highlighting its potential as a therapeutic strategy for reducing corneal fibrosis associated with keratoconus. Full article

Cardiovascular complications increasingly challenge survivors of urological cancers, given the cardiotoxicity of therapies such as androgen deprivation, vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and chemotherapy. This narrative review addresses the complex crosstalk between urological cancer treatment and cardiovascular disease. It summarizes cardiovascular toxicities linked to major antineoplastic agents, explores underlying mechanisms including metabolic and immune-mediated effects, and proposes strategies for surveillance, diagnosis, and management. Highlighting the need for multidisciplinary collaboration, it outlines future directions for research to optimize cardiovascular outcomes in this high-risk population. The increasing complexity of cardiovascular care in patients with urological malignancies highlights the need for closer collaboration between cardiologists, urologists, and oncologists, with uro-cardio-oncology emerging as an important multidisciplinary field. Full article

Modeling the dynamics of three tumor cell populations, i.e., sensitive, persister, and resistant tumor cells, during molecularly targeted therapy with tyrosine kinase inhibitors (TKIs) would be valuable for adjusting treatment plans for patients with epidermal growth factor receptor-mutated non-small cell lung cancer (EGFR-mt NSCLC). We hypothesized the time-variant tumor growth trajectories (TGTs) of patients with stage IV EGFR-mt NSCLC for the three tumor cell populations could be expressed using differential models after several follow-up computed tomography examinations. We aimed to propose differential models for TGTs in three cell populations from patients with EGFR-mt NSCLC treated with an EGFR-TKI (osimertinib). We selected two differential equations—Bertalanffy–Pütter (BP) and Gompertz—to develop TGT models. The parameters of the models were optimized based on a dual annealing method within parameter ranges determined using synthetic patient data. Using CT examinations that were not employed for model fitting, the mean absolute percentage errors (MAPEs) for BP-based and Gompertz-based models were 36.1 ± 40.2% and 43.9 ± 60.1%, respectively, for three follow-up computed tomography (FCT) examinations, which indicated no statistically significant difference (p = 0.61). This study suggests that the proposed BP-based and Gompertz-based differential models could have the potential to express TGTs in patients with stage IV EGFR-mt NSCLC treated with EGFR-TKIs after three follow-up CT examinations, although MAPEs should be mitigated in future works. Full article

Background: Anaplastic Lymphoma Kinase (ALK) is an oncogenic receptor tyrosine kinase implicated in several cancers. Despite the clinical success of ALK inhibitors, acquired resistance continues to drive the search for novel chemotypes. We developed a multiclass machine learning framework to classify ALK inhibitory activity using a curated ChEMBL dataset. Methods: Models were built using 2D molecular descriptors together with MACCS and ECFP4 fingerprints. Three widely used algorithms, Support Vector Machine (SVM), Random Forest (RF), and XGBoost, were applied for model development. Results: RF and XGBoost models demonstrated the best performance, achieving accuracies of ~0.75–0.79 with consistently high ROC–AUC values, particularly for fingerprint-based features. Bemis–Murcko scaffold analysis identified enriched chemotypes and underexplored scaffolds for further prioritization. The validated models were subsequently used to screen the Maybridge library, and compounds predicted to possess potential ALK inhibitory activity were prioritized for further computational evaluation. Applicability-domain filtering confirmed that the selected compounds occupied the predicted ALK inhibitor chemical space across multiple activity classes. The shortlisted compounds were subsequently evaluated by molecular docking to characterize their binding modes and interactions. Three candidate hits (SCR00078, SCR00073, and AW01085) were selected for further evaluation using 500 ns molecular dynamics simulations alongside the reference inhibitor Brigatinib. Simulation analyses revealed stable protein–ligand complexes and reduced conformational fluctuations relative to apo ALK, while MM/PBSA calculations identified SCR00078 and AW01085 as the most favorable binders. Conclusions: This integrated ML-to-simulation workflow prioritizes structurally novel candidate hits with predicted ALK inhibitory activity and provides an effective strategy for scaffold discovery and hit prioritization. Full article

Chronic spontaneous urticaria (CSU) is a mast cell-driven disorder defined by recurrent wheals, angioedema, or both, persisting for longer than six weeks without an identifiable external trigger. Second-generation H1-antihistamines remain first-line therapy, yet a large share of patients stay symptomatic after the dose is raised up to fourfold, and for more than a decade, omalizumab was the only targeted option for those who failed antihistamines. This began to change in 2025, when the interleukin-4 receptor alpha (IL-4Rα) antagonist dupilumab and the oral, covalent Bruton tyrosine kinase (BTK) inhibitor remibrutinib were approved for antihistamine-refractory CSU within months of one another, while the anti-KIT monoclonal antibody barzolvolimab, which depletes mast cells, advanced into the largest phase 3 program the disease has seen. This narrative review outlines the guideline framework that still anchors CSU care, appraises the pivotal efficacy and safety data for omalizumab, dupilumab, remibrutinib, and barzolvolimab, and considers how these mechanistically distinct agents might be positioned and sequenced. The widening choice makes individualized, mechanism-informed treatment a realistic goal, but it also sharpens unresolved questions about patient selection, optimal treatment duration in a naturally remitting disease, and the long-term safety of newer oral and mast cell-depleting approaches. Full article