Search Results (831)

Background: Rhabdoid tumor of the kidney (RTK) is a highly aggressive pediatric malignancy characterized by biallelic SMARCB1 loss, resulting in aberrant MYC pathway activation and cell cycle regulation. MYC-activated tumors are vulnerable in splicing functions and sensitive to splicing inhibitors. Therefore, in this study, cyclin-dependent kinase 11 (CDK11), which regulates both cell cycle and RNA splicing, was tested as a therapeutic target in RTK. Methods: CDK11A/B expression was analyzed using the TARGET-RT database. The therapeutic efficacy of the CDK11 inhibitor OTS964 was evaluated in two RTK cell lines (G401 and JMU-RTK-2) and a JMU-RTK-2 xenograft mouse model. Cytotoxicity, apoptosis, cell cycle, and RNA splicing were examined using the Sulforhodamine B assay, immunoblotting, flow cytometry, and RT-PCR. Results: CDK11B, but not CDK11A, was significantly upregulated in RTK and correlated with the poor survival. OTS964 inhibited RTK cell growth in vitro with the IC50 of 33.1 nM (G401) and 19.3 nM (JMU-RTK-2) and significantly prolonged survival in vivo (median survival: 46.5 vs. 37.0 days, p < 0.01) without marked toxicity. Mechanistically, OTS964 induced G2/M cell cycle arrest and p53 upregulation, disrupted RNA splicing via SF3B1 dephosphorylation, and ultimately led to apoptosis through caspase-3 activation. Conclusions: CDK11 inhibition by OTS964 effectively suppresses RTK growth through cell cycle arrest and RNA splicing inhibition, leading to apoptosis. OTS964 shows potent anti-tumor activity and tolerability, supporting CDK11 as a promising therapeutic target for RTK and related SMARCB1-deficient cancers. Full article

Estrogen receptor-positive (ER⁺) breast cancer represents the most prevalent molecular subtype of breast cancer, characterized by hormone-dependent growth, relatively indolent progression, and a pronounced tendency to metastasize to bone. While endocrine therapies remain the cornerstone of treatment, a significant proportion of ER⁺ tumors eventually develop resistance, culminating in distant metastases—most frequently to the bone. Bone metastasis substantially compromises patient survival and quality of life, highlighting the critical need to elucidate its molecular underpinnings. Recent multi-omics and mechanistic studies have shed light on the complex interplay between tumor-intrinsic signaling pathways, such as dysregulated ER signaling, PI3K/AKT/mTOR, TGF-β, and Hippo pathways, and the bone microenvironment, including osteoclast activation, immune suppression, and stromal remodeling. This review systematically summarizes the current understanding of the molecular mechanisms driving bone metastasis in ER⁺ breast cancer, with a particular focus on tumor–bone microenvironment crosstalk and key regulatory pathways. Additionally, we discuss recent advances in therapeutic strategies, encompassing next-generation endocrine therapies, CDK4/6 inhibitors, bone-targeted agents, and pathway-specific inhibitors. Together, these insights pave the way for more effective and personalized interventions against ER⁺ breast cancer with bone involvement. Full article

Background: Canine mammary carcinoma (CMC) is the most common malignant tumour in female dogs and, due to its similarities, is a valuable comparative model for human breast cancer. Kinase inhibitors have revolutionised the treatment of human breast cancer; their use in veterinary oncology remains marginal. Aim: This review summarises the current knowledge of kinase signalling pathways in CMC and assesses which kinase inhibitors approved for human use have potential in veterinary medicine. Methods: A systematic search of the PubMed database from 1985 to 2025 was performed, focusing on kinase-targeted therapies in both human and canine mammary carcinomas. Data were categorised according to molecular target, clinical approval status, and available preclinical or clinical veterinary evidence. Results: Key molecular pathways targeted by kinase inhibitors are conserved across species, supporting translational opportunities. In vitro studies demonstrate that palbociclib, alpelisib, everolimus, and lapatinib inhibit growth and signalling in CMC cell lines. Clinical trials have not been conducted. Conclusions: Approved kinase inhibitors for human use have untapped therapeutic potential in veterinary oncology. Translational research, including xenograft and organoid models, followed by clinical trials in dogs, is required. Gaining this knowledge could lead to targeted treatment for dogs while advancing comparative understanding of mammary cancer biology across species. Full article

Background/Objectives: Despite initial sensitivity to ET, most patients with HR+/HER2− breast cancer develop resistance. A key molecular mechanism of endocrine resistance in HR+ breast cancer involves dysregulation of the cyclin D–CDK4/6–Rb signaling axis, which controls the transition from the G1 to S phase of the cell cycle. Introducing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) has changed therapeutic paradigms in HR+/HER2− breast cancer, as their synergistic use with endocrine therapy significantly prolongs progression-free survival (PFS) and effectively mitigates clinically relevant endocrine resistance in this patient population compared to ET alone. The aim of our study was to evaluate patients’ clinical characteristics, the clinical effectiveness of treatment, measured by progression-free survival (PFS), and the safety profile of combined ribociclib (CDK4/6i) and standard endocrine therapy (aromatase inhibitor) as a first-line treatment for patients with HR+/HER2− advanced or metastatic breast cancer at the Clinic of Oncology, University Clinical Centre Nis, Serbia. Methods: In this study, we present a retrospective prospective analysis of all patients with metastatic HR+/HER2− breast cancer treated with a combination of ribociclib and aromatase inhibitors in the first-line treatment of metastatic HR+/HER2− BC between June 2022 and January 2025, with a follow-up completed in October 2025. A total of 132 patients who met the criteria were included. Results: The median progression-free survival (PFS) in the entire group was 30 months, while the 12-, 24-, and 36-month PFS were 82.15%, 72.24%, and 28.75%, respectively. The overall response rate (ORR) was 41.7%, while the clinical benefit rate (CBR) was 89.3%. There was no statistically significant difference in PFS with respect to tumor grade (p = 0.54), Ki 67 level (<20% vs. >20%, p = 0.83), or the type of adjuvant endocrine therapy used (tamoxifen vs. AI) It is important to emphasize that female patients who had not previously received chemotherapy had a better response to ribociclib compared to those who had (33 m vs. 28 m, p = 0.05). Although a numerical difference in PFS was found in patients with bone-only metastases compared to those with metastases in other organs, the difference was not statistically significant (PFS 33 m vs. 30 m, p = 0.27;), and efficacy was consistent across menopausal status groups. The most common adverse effect was neutropenia, occurring in 89.4% of patients, 47.7% of whom presented with grade 3 or 4. As for hepatotoxicity, transaminase increase occurred in 25 patients (18.8%), 5 of whom (3.8%) were grade 3–4, and QTc interval prolongation occurred in 5.3% of patients. Conclusions: The results in terms of PFS and AEs are consistent with those of pivotal studies and real clinical practice data, but a direct comparison is not possible due to differences in patient populations. Ribociclib once again demonstrated efficacy in all patient subgroups and remains the gold standard, alongside ET, for first-line HR+/HER2-negative mBC. Full article

Thalamic gliomas are among the most challenging pediatric brain tumors due to the delicate functions of the thalamus. Limited surgical intervention leads to the use of adjuvant therapies, including targeted therapy. Thalamic gliomas can be divided into two distinct groups: diffuse midline glioma (DMG) and low-grade glioma (LGG). The most common mutations that can be targeted for treatment are the KIAA1549-BRAF fusion; BRAF V600E mutation; EGFR, FGFR, PDGFR, NTRK, and CDK4/6 mutations; other MAP kinase pathway alterations; and PI3K/AKT/mTOR activation. The bithalamic high-grade glioma especially demonstrates EGFR mutations which makes it a distinct entity. Targeted therapy, including tyrosine kinas inhibitors has been shown to improve the overall survival compared to conventional therapy in certain situations. Demonstrating the mutation carried by the tumor is very critical in this regard. The purpose of this article is to focus on the treatment of thalamic glioma in pediatric patients in light of molecular information. Full article

Background: In malignant pleural mesothelioma, epithelioid histology is traditionally considered a favorable prognostic marker. However, it remains clinically undetermined whether the intensity of an oncogenic insult can disrupt this link. Radiation-induced cases serve as an unconfounded biological model to dissect such trajectories masked by asbestos confounding. Methods: We performed an Individual Patient Data (IPD) synthesis of 20 strictly asbestos-unexposed human cases, applying clinically established dose stratification (intermediate: 20–45 Gy vs. high: >45 Gy). To confirm the observed pattern, we examined data from 829 dogs in the Colorado State University (CSU) Beagle Study. Results: In the intermediate-dose group (n = 13), a significant positive correlation persisted between age at radiotherapy and the latent period (ρ = 0.567, p = 0.043). Conversely, high-dose exposure (>45 Gy) showed a disruption of this age-dependent pattern, with a trend toward inverse correlation (ρ = −0.754, p = 0.084). Interaction analysis confirmed a statistically significant divergence between these dose-dependent trends (p = 0.005). The CSU Beagle Study (n = 829) demonstrated the physical basis of this phenomenon: in the canine model, high-dose exposure (≥0.74 Gy) triggered a “Step-Jump” in cumulative incidence (30.4% at 0.5 years), indicating instantaneous carcinogenic onset distinct from cumulative biological aging. Conclusions: This kinetic divergence points to a “Diagnostic Trap.” We propose a ‘Single- to Double-Brake’ framework where intermediate doses preserve age-dependent progression, whereas high doses likely trigger catastrophic genomic failure (chromothripsis) that bypasses the time required for morphological dedifferentiation. Consequently, morphologically indolent epithelioid tumors in high-dose survivors may harbor aggressive molecular profiles not predicted by histology alone, necessitating risk-stratified precision surveillance. Full article

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for estrogen receptor-positive (ER+) breast cancer, yet resistance remains a major clinical challenge. Although CDK4/6i induce G₁ arrest and therapy-induced senescence (TIS), the exact nature of this senescent state and its contribution to resistance are not well understood. To explore this, we developed palbociclib- (2PR, 9PR, TPR) and abemaciclib- (2AR, 9AR, TAR) resistant ER+ breast cancer sublines through prolonged drug exposure over six months. Resistant cells demonstrated distinct phenotypic alterations, including cellular senescence, reduced mitochondrial membrane potential, and impaired glycolytic activity. Cytokine profiling and enzyme-linked immunosorbent assay (ELISA) validation revealed a non-canonical senescence-associated secretory phenotype (SASP) characterized by elevated growth/differentiation factor 15 (GDF-15) and serpin E1 (plasminogen activator inhibitor-1, PAI-1) and absence of classical pro-inflammatory interleukins, including IL-1α and IL-6. IL-8 levels were significantly elevated, but no association with epithelial–mesenchymal transition (EMT) was observed. Resistant cells preserved their epithelial morphology, showed no upregulation of EMT markers, and lacked aldehyde dehydrogenase 1-positive (ALDH1+) stem-like populations. Additionally, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) was strongly upregulated in palbociclib-resistant cells. Together, these findings identify a distinct, non-canonical senescence phenotype associated with CDK4/6i resistance and may provide a foundation for identifying new vulnerabilities in resistant ER+ breast cancers through targeting SASP-related signaling. Full article

(1) Background: All-trans retinoic acid (ATRA) has transformed the treatment of acute promyelocytic leukemia (APL) by inducing terminal myeloid differentiation. However, its efficacy in non-APL acute myeloid leukemia (AML) is limited. Exploring combination strategies that enhance ATRA-induced differentiation may broaden its therapeutic potential. (2) Methods: A literature search of PubMed using the keywords “ATRA,” “myeloid,” and “differentiation inducer or enhancer” identified more than 500 published papers as of November 2025. Pre-clinical and clinical studies were reviewed, with a focus on mechanisms, combination partners, and translational relevance. (3) Results: Clinical evidence confirms that ATRA combined with arsenic trioxide or epigenetic modulators achieves high remission rates in APL and selected AML subtypes. Pre-clinical studies show synergistic differentiation effects when ATRA is combined with CDK and kinase inhibitors, nucleotide synthesis inhibitors, DNA-damaging agents, Bcl-2/MDM2 inhibitors, proteasome inhibitors, cytokines, glycosylation modifiers, natural products, and antibiotic-derived compounds. Mechanistically, these combinations modulate key signaling pathways (MAPK, Akt, JAK/STAT), stabilize RARα, remodel chromatin, and perturb nucleotide metabolism. Although translation to non-APL AML remains limited, these findings provide a rational basis for future clinical trials. (4) ATRA-based combination therapies represent a promising strategy to extend differentiation therapy beyond APL. This review, authored solely by the investigator, highlights molecular targets and potential enhancers warranting further clinical evaluation in AML. Full article

Axillary management in early-stage, HER2-negative, hormone receptor-positive breast cancer has undergone major changes in recent years. While axillary lymph node dissection (ALND) was once considered essential for staging and regional control, increasing evidence supports the safety of surgical de-escalation in selected patients. At the same time, systemic therapies such as CDK4/6 and PARP inhibitors rely on nodal burden to define eligibility, raising new challenges in balancing oncologic benefit with treatment-related morbidity. This narrative review summarizes current strategies in axillary management for patients undergoing upfront surgery for HR-positive, HER2-negative early breast cancer. It explores the role of sentinel lymph node biopsy (SLNB), the indications for ALND, the integration of adjuvant systemic therapy, and the emerging role of radiotherapy and predictive tools in guiding individualized treatment decisions. Key randomized trials including Z0011, AMAROS, SENOMAC, SOUND, and INSEMA have demonstrated that omission of ALND is safe in patients with limited nodal involvement, especially when combined with whole-breast or regional nodal radiotherapy. However, trials such as MonarchE and OlympiA have introduced systemic therapies whose indications are closely tied to nodal status, prompting reconsideration of the extent of axillary staging. Advances in imaging and risk stratification tools offer new avenues for safely limiting surgical intervention while preserving access to systemic options. In conclusion, modern axillary management in HR-positive, HER2-negative breast cancer involves navigating the intersection between de-escalated surgery and risk-adapted systemic therapy. Future strategies should prioritize individualized care, incorporating tumor biology, imaging findings, and patient preferences, with multidisciplinary collaboration playing a central role in optimizing outcomes. Full article

The 2025 Canadian Breast Cancer Symposium (CBCS) brought together patients, clinicians and researchers from across Canada to discuss advances shaping personalized breast cancer care. Key updates in systemic therapy highlighted expanding treatment options, including CDK4/6 inhibitors, oral SERDs, PI3K/AKT-targeted therapies, and antibody–drug conjugates across early and metastatic settings. Radiation oncology sessions emphasized treatment de-escalation, featuring evidence for ultra-hypofractionation, selective omission of nodal irradiation, and stereotactic strategies to manage oligoprogression. Surgical presentations focused on reducing morbidity through tailored axillary management and emerging techniques to prevent lymphedema. Advances in the management of central nervous system metastases underscored the growing synergy between stereotactic radiotherapy and CNS-active systemic therapies. Informed by patient testimony and advocacy perspectives, experts reflected on persistent gaps in diagnosis, access, and survivorship that shape priorities for future improvements. Together, these insights outline key directions that help to refine clinical practice and guide future research. Full article

Background/Objectives: Cyclin-dependent kinase 4/6 inhibitors combined with endocrine therapy have become the standard of care for HR+/HER2− metastatic breast cancer. Given the metabolic functions of CDK4/6 and the endocrine activity of adipose tissue, body mass index has been proposed as a potential prognostic or predictive factor in this setting. This systematic review aimed to summarize current evidence on the association between BMI and treatment outcomes in HR+/HER2− MBC patients receiving CDK4/6i. Methods: A systematic literature search was conducted in PubMed and Scopus databases, covering publications from 2015 to 2025. We included real-world studies and clinical cohorts reporting survival outcomes of HR+/HER2− MBC patients treated with CDK4/6i in relation to BMI and other body composition parameters. Results: From 69 records identified, 14 studies met the inclusion criteria. Findings were heterogenous; four studies reported improved survival outcomes in higher BMI patients, whereas most identified no significant association. Studies incorporating computed tomography-based metrics demonstrated that body composition parameters such as visceral adiposity and skeletal muscle area were more reliable predictors of prognosis than BMI alone. Conclusions: Our findings indicate that BMI as a standalone metric is an insufficient predictor of clinical outcomes or treatment response for those receiving CDK4/6i, highlighting the need for precise body composition evaluation. More detailed anthropometric and metabolic profiling could clarify the clinical significance of adiposity in HR+/HER2− MBC. Full article

Precision medicine has reshaped the clinical management of prostate cancer by integrating comprehensive genomic profiling, biomarker-driven patient stratification, and the development of molecularly targeted therapeutics. Advances in next-generation sequencing have uncovered diverse genomic alterations—including homologous recombination repair defects, MSI-H/MMRd, PTEN loss, BRCA1/BRCA2 mutations, ATM alterations, SPOP mutations, and molecular hallmarks of neuroendocrine differentiation—that now inform individualized treatment decisions. This review synthesizes established clinical evidence with emerging translational insights to provide an updated and forward-looking overview of precision oncology in prostate cancer. Landmark trials of PARP inhibitors and PSMA-targeted radioligand therapy have redefined treatment standards for biomarker-selected patients. Concurrently, efforts to optimize immune checkpoint inhibition, AKT pathway targeting, and rational combinations with androgen receptor pathway inhibitors continue to expand therapeutic possibilities. Rapidly evolving investigational strategies—including bipolar androgen therapy (BAT), immunotherapeutic approaches for CDK12-altered tumors, targeted interventions for SPOP-mutated cancers, and epigenetic modulation such as EZH2 inhibition for neuroendocrine prostate cancer—further illuminate mechanisms of tumor evolution, lineage plasticity, and treatment resistance. Integrating multi-omics technologies, liquid biopsy platforms, and AI-assisted imaging offers new opportunities for dynamic disease monitoring and biology-driven treatment selection. By consolidating current clinical practices with emerging experimental directions, this review provides clinicians and researchers with a comprehensive perspective on the evolving landscape of precision medicine in prostate cancer and highlights future opportunities to improve patient outcomes. Full article

Cyclin-dependent kinase 9 (CDK9) is a key regulator of transcriptional elongation and DNA repair, supporting cancer cell survival by sustaining the expression of oncogenes and anti-apoptotic proteins. Its overexpression in multiple malignancies makes it an attractive target for anticancer therapy. Here, we report a machine learning (ML) based approach to identify novel CDK9 inhibitors. Through systematic data collection and preprocessing, seventy predictive models were developed using five algorithms, two classification settings, and seven molecular representations. The best-performing model was employed to guide a virtual screening (VS) campaign, resulting in the identification of 14 compounds promising for their potential inhibitory effect. Upon enzymatic assays, two molecules with inhibitory activity in the low micromolar range were selected as promising candidates and further tested in three cancer cell lines with distinct genetic backgrounds. These experiments led to the identification of a novel compound exhibiting interesting therapeutic potential, both as a single agent and in combination with Camptothecin (CPT), revealing varying response profiles across the tested cell lines. These results illustrate the power of integrating ML within anticancer drug discovery pipelines and represent a valuable starting point for the development of novel CDK9 inhibitors. Full article

Background/Objectives: Cancer is among the leading causes of mortality worldwide. In 2022 alone, the global cancer death toll stood at 9.74 million. Projections indicate that this figure will rise to 10.4 million by 2025. Methods: A new series of benzimidazolone-bridged hybrid compounds containing thiophene, furan, oxadiazole, piperazine, and coumarin moieties was synthesized and structurally characterized by ¹H-NMR, ¹³C-NMR (APT), and elemental analysis. Their cytotoxic effects were evaluated by MTT assay against human lung (A549), human breast (MCF-7), and human cervical (HeLa) cancer cell lines, and the non-cancerous HEK293 cell line after 48 h exposure over a concentration range of 0.5–250 µM. IC₅₀ values were determined, and Selectivity Indexes (SI) were calculated using HEK293 as the reference normal cell line. Molecular docking studies were carried out using the Glide XP protocol against VEGFR2 (PDB ID: 4ASD) and CDK4–Cyclin D3 (PDB ID: 7SJ3), with sorafenib and abemaciclib as reference inhibitors. Results: The results of anticancer activity were compared with doxorubicin (IC₅₀ ± SD (µM)/SI: 4.3 ± 0.2/1.20 for A549, 6.4 ± 0.37/0.77 for MCF-7, 3.4 ± 0.19/1.54 for HeLa), a drug used for cancer chemotherapy. The structures of the newly synthesized hybrid compounds were identified by ¹H-NMR, ¹³C-NMR (APT), and elemental analysis data. These hybrid compounds represent a promising class of anticancer agents. Several compounds demonstrated marked and concentration-dependent cytotoxicity across all cancer cell lines, with HeLa cells showing the highest overall sensitivity. The introduction of an oxadiazole ring (compound 7) and coumarin substituents (compounds 12b–12d) markedly improved anticancer activity and selectivity, yielding low-micromolar IC₅₀ values in HeLa cells (10.6–13.6 µM) and high Selectivity Indexes (SI = 2.0–3.63). Compound 6 also exhibited balanced potency across A549, MCF-7, and HeLa cells (IC₅₀ = 28.3–31.2 µM) with SI values ≥ 2.0. Compound 9 showed strong cytotoxicity across all cancer cell lines; its moderate SI values indicate lower discrimination between malignant and non-malignant cells. Taken together, these findings identified compounds 7, 12b–12d, 6, and 12c as the most promising benzimidazolone-based candidates, displaying both potent cytotoxicity and favorable selectivity over non-malignant HEK293 cells. Conclusions: Among the synthesized molecules, the oxadiazole derivative (7) and the coumarin-based hybrids (12b–12d) exhibited the strongest combination of cytotoxic activity and selectivity, reflected by their low IC₅₀ values and high SI ratios. Notably, compound 12c combined strong biological activity with the highest predicted VEGFR2 affinity in the series, highlighting it as a particularly promising scaffold. While compound 9 exhibited excellent docking scores toward both VEGFR2 and CDK4, its lower selectivity suggests a need for further structural refinement. Overall, the biological and computational findings converge to identify these benzimidazolone hybrids as credible lead candidates for future anticancer optimization. Full article

Objective: CDK4/6 inhibitors constitute standard first-line therapy for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). We investigated real-world predictors of overall survival (OS), with particular focus on high ER expression (≥90%). Methods: In this multicenter, retrospective study, we analyzed 603 HR-positive/HER2-negative MBC patients treated with CDK4/6 inhibitors (ribociclib or palbociclib) between May 2020 and June 2024. We evaluated demographic, clinical, and pathological factors for their impact on OS using univariate and multivariate Cox regression analyses. Results: In univariate analysis, significantly longer OS was observed in endocrine therapy-naive patients (median OS: 51.0 vs. 33.3 months; p < 0.001), those without liver metastases (50.0 vs. 34.0 months; p = 0.019), bone-only metastases (57.7 vs. 40.5 months; p = 0.022), and PR-positive patients (50.0 vs. 36.0 months; p = 0.037). Patients with ER expression ≥90% showed a strong trend toward longer OS (49.0 vs. 41.0 months; p = 0.072). In multivariate analysis, endocrine therapy naivety (p = 0.045) and high ER expression (≥90%) (p = 0.031) emerged as independent predictors of superior OS. Conclusions: Our study identifies treatment naivety and exceptionally high ER expression (≥90%) as key independent predictors of prolonged OS in CDK4/6 inhibitor-treated MBC patients. These findings underscore the importance of early CDK4/6 inhibitor implementation and suggest that quantitative ER assessment may refine patient selection beyond conventional positivity thresholds. Full article