Search Results (779)

Triple-negative breast cancer (TNBC) is a highly aggressive and therapeutically challenging subtype of breast cancer due to its lack of estrogen receptors, progesterone receptors, and HER2 (Human epidermal growth factor receptor 2) expression, which severely limits available treatment options. Recently, Simvastatin—a widely used HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor for hyperlipidemia—has garnered interest for its potential anticancer effects. This study investigates the therapeutic potential of Simvastatin in triple-negative breast cancer (TNBC). The results demonstrate that Simvastatin significantly inhibits the proliferation of TNBC cells, particularly MDA-MB-231, in a dose- and time-dependent manner. Mechanistically, Simvastatin primarily induces G1 phase cell cycle arrest to exert its antiproliferative effects, with no significant evidence of apoptosis or necrosis. These findings support the potential repositioning of Simvastatin as a therapeutic agent to suppress TNBC cell growth. Further analysis shows that Simvastatin downregulates cyclin-dependent kinase 4 (CDK4), a key regulator of the G1/S cell cycle transition and a known marker of poor prognosis in breast cancer. These findings highlight a novel, apoptosis-independent mechanism of Simvastatin’s anticancer action in TNBC. Importantly, given that many breast cancer patients also suffer from hyperlipidemia, Simvastatin offers dual therapeutic benefits—managing both lipid metabolism and tumor cell proliferation. Thus, Simvastatin holds promise as an adjunctive therapy in the treatment of TNBC and warrants further clinical investigation. Full article

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of tumors with a complex molecular profile. Despite therapeutic advances, patient prognosis remains poor, emphasizing the need for more effective treatment strategies. Traditional chemotherapy, with cisplatin and 5-fluorouracil (5-FU), remains the gold standard but is limited by toxicity and tumor resistance. Immunotherapy, particularly immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1), has improved overall survival, especially in patients with high PD-L1 expression. In parallel, targeted therapies such as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors—which impair DNA repair and increase replication stress—have shown promising activity in HNSCC. Cyclin-dependent kinase (CDK) inhibitors are also under investigation due to their potential to correct dysregulated cell cycle control, a hallmark of HNSCC. This review aims to summarize current and emerging pharmacotherapies for HNSCC, focusing on chemotherapy, immunotherapy, and PARP and CDK inhibitors. It also discusses the evolving role of targeted therapies in improving clinical outcomes. Future research directions include combination therapies, nanotechnology-based delivery systems to enhance treatment specificity, and the development of diagnostic tools such as PARP1-targeted imaging to better guide personalized treatment approaches. Full article

Background/Objectives: This study aimed to assess real-world toxicity and efficacy data of patients with early and advanced breast cancer (BC) who received treatment with abemaciclib. Methods: This was a prospective/retrospective multi-institutional collection of clinicopathological, toxicity, and outcome data from patients with early or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC who received treatment with abemaciclib in combination with endocrine therapy in departments of oncology in Greece. Treatment combinations of abemaciclib with any endocrine therapy were accepted. The primary end point was toxicity rate in all patients of the study. Results: From June/2021 to May/2024, 245 women received abemaciclib/endocrine combination therapy; the median age was 57 years. Of these, 169 (69%) received abemaciclib as adjuvant therapy for early-stage disease, while 76 (31%) were treated for advanced BC. At the time of the data cutoff, 133 (84.7%) patients remained in the 2-year treatment period. The most common adverse event (AE) was diarrhea (51%), primarily Grade ≤ 2. Dose modifications due to AEs were required in 19.2% of cases, while treatment discontinuation occurred in 5.1%. There was no difference in dose modification/discontinuation rates between older patients (>65 years) and the remaining patients. For early-stage BC patients, the 2-year DFS and OS rates were 90.8% and 100%, respectively. In patients with advanced cancer (70, 30.8%), 1-year PFS and OS rates were 78% and 96.3%, respectively. Conclusions: This study confirms the safety and effectiveness of abemaciclib in alignment with registrational trials offering valuable insights into toxicity management and clinical outcomes in routine practice without identifying new safety concerns. Clinical Trial Registration: ClinicalTrials.gov NCT04985058. Full article

Advances in molecular diagnostics have enabled precision medicine approaches in pediatric neuro-oncology, with small-molecule drugs emerging as promising therapeutic candidates targeting specific genetic and epigenetic alterations in central nervous system (CNS) tumors. This review provides a focused overview of several small-molecule agents under investigation or in early clinical use, including ONC201, tazemetostat, vorasidenib, CDK inhibitors, selinexor, and aurora kinase A inhibitors, among others. Highlighted are their mechanisms of action, pharmacokinetic properties, early efficacy data, and tolerability in pediatric populations. Despite encouraging preclinical and early-phase results, most agents face limitations due to study heterogeneity, lack of large-scale pediatric randomized trials, and challenges in drug delivery to the CNS. The review underscores the critical need for robust prospective clinical trials for the integration of these therapies into pediatric neuro-oncology care. Full article

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder with a pressing need for novel therapeutics. However, current medications only offer symptomatic relief, without tackling the underlying pathology. To explore the bioactive potential of marine-derived fungi, this study focused on Aspergillus terreus C23-3, a strain isolated from the coral Pavona cactus in Xuwen County, China, which showed a richer metabolite fingerprint among the three deposited A. terreus strains. AntiSMASH analysis based on complete genome sequencing predicted 68 biosynthetic gene clusters (BGCs) with 7 BGCs synthesizing compounds reported to have anti-AD potential, including benzodiazepines, benzaldehydes, butenolides, and lovastatin. Liquid chromatography coupled with mass spectrometry (LC-MS)-based combinational metabolomic annotation verified most of the compounds predicted by BGCs with the acetylcholinesterase (AChE) inhibitor territrem B characterized from its fermentation extract. Subsequently, molecular docking showed that these compounds, especially aspulvione B1, possessed strong interactions with AD-related targets including AChE, cyclin-dependent kinase 5-p25 complex (CDK5/p25), glycogen synthase kinase-3β (GSK-3β), and monoamine oxidase-B (MAO-B). In conclusion, the genomic–metabolomic analyses and molecular docking indicated that C23-3 is a high-value source strain for anti-AD natural compounds. Full article

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently “cold” tumor microenvironment into a “hot” immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy. Full article

Background and Objective: We aim to determine the efficacy and the factors associated with the effectiveness of first-line CDK4/6i (ribociclib or palbociclib) treatment in HR-positive, HER2-negative MBC patients. Materials and Methods: This is a retrospective, cross-sectional, and descriptive study. Ninety patients with metastatic breast cancer receiving CDK 4/6i treatment from three different oncology clinics were included in this study. Results: Of the patients, 56 (62.2%) received ribociclib, and 34 (37.8%) were administered palbociclib. There was no significant difference between the groups regarding age, gender, comorbidities, ECOG performance status, or menopausal status (p > 0.05). The cut-off values for ER, PR, and Ki-67 levels were determined via ROC curve analysis. These values were found to be 80% for ER levels, 50% for PR levels, and 30% for Ki-67 levels. PFS was significantly longer for patients with ER levels greater than 80% and Ki-67 expression levels less than 30% according to multivariate analysis. Among the patients included in our study, the median PFS was 22.41 months for the patients with Ki-67 levels of 30% and above, while the median PFS was 17.24 months for the patients with ER levels of 80% and below. Among the patients with a combined ER of 80% or less and a Ki-67 of 30% or more, the median PFS was 12.42 months (p < 0.001). Conclusions: This study demonstrates that CDK4/6i therapies led to longer PFS among patients with ER levels greater than 80% and Ki-67 expression levels less than 30%. It is essential to determine which patient group benefits more from first-line CDK4/6is therapy. Full article

The adjuvant treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) early breast cancer (EBC) is rapidly evolving, with a diverse range of therapeutic options—including endocrine therapies, bisphosphonates, ovarian function suppression, olaparib, CDK4/6 inhibitors, and emerging agents such as immunotherapy. While these advances have markedly improved patient outcomes, they also introduce challenges related to implementation, monitoring, and resource allocation. Notably, therapies like CDK4/6 inhibitors require particularly close monitoring, creating logistical and capacity challenges for medical oncologists, whose workloads are already stretched due to rising cancer incidence and treatment complexities. These challenges underscore the need for innovative care delivery solutions to ensure patients with EBC continue to receive optimal care. This paper offers a comprehensive guide—a playbook—of multidisciplinary-team-based care models designed to optimize adjuvant treatment delivery in EBC. Drawing on real-world evidence and successful applications across Canadian centers, we explore models led by nurses, nurse practitioners (NPs), general practitioners in oncology (GPO), and pharmacists. Each model leverages the unique expertise of its team to manage treatment toxicities, facilitate adherence, and enhance patient education, thereby promoting effective and sustainable care delivery. Importantly, these models are not intended to compete with one another, but rather to serve as a flexible recipe book from which breast cancer care teams can draw strategies tailored to their local resources and patient needs. By detailing implementation strategies, benefits, and challenges—in many instances supported by quantitative metrics and economic evaluations—this work aims to inspire care teams nationwide to optimize the adjuvant management of patients with HR+, HER2– EBC. Full article

CLL is the most prevalent adult leukemia in Western countries, characterized by the accumulation of monoclonal B lymphocytes. Over the past decade, the therapeutic landscape for CLL has undergone significant transformations, primarily due to the introduction of targeted small molecular therapies like BTK inhibitors and BCL-2 inhibitors, that have improved patient outcomes drastically. Despite significant advances, long-term disease management remains challenging for patients with double-refractory CLL, where responses with subsequent therapies are short-lived. Resistance to these therapies can arise through several mechanisms like kinase-altering BTK mutations, alterations in the BCL-2 pathway, and adaptations within the tumor microenvironment, necessitating the exploration of new therapeutic options. This review provides an in-depth overview of the promising novel treatment approaches under investigation in CLL, focusing on advanced cellular therapies (CAR T-cell therapy), T-cell engagers, new monoclonal antibodies, and various next-generation small molecule inhibitors including BTK degraders, PI3K inhibitors, MALT1 inhibitors, c-MYC inhibitors, CDK9 inhibitors, and agents targeting angiogenesis and DNA damage repair. In this review, we will discuss the novel therapeutic targets and agents as well as ongoing trials, emphasizing the potential of these treatments to overcome resistance and meet the unmet needs of patients, particularly those with double-refractory CLL. Full article

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. Methods: In this study, the aqueous root extract of Thottea siliquosa, a traditionally used medicinal plant, was evaluated for its potential as a natural CDK4/6 inhibitor. Phytochemical profiling using GC-MS identified bioactive compounds, which were subsequently subjected to molecular docking, ADME prediction, and in vitro cell-based assays using HCT116 and L929 cells. Results: The docking results revealed that Isocorydine (−7.4 kcal/mol for CDK4 and −7.2 kcal/mol for CDK6) and Thunbergol (−6.5 kcal/mol for CDK4 and −7.0 kcal/mol for CDK6) exhibited promising binding affinities comparable to standard CDK inhibitors, Palbociclib (−7.2, −8.3 kcal/mol) and Ribociclib (−7.1, −8.1 kcal/mol). Among the other tested natural compounds, Squalene (−7.1 kcal/mol for CDK4) and 2-palmitoylglycerol (−5.2 kcal/mol for CDK4, −4.9 kcal/mol for CDK6) demonstrated moderate binding affinities. ADME analysis confirmed favorable drug-like properties with minimal toxicity alerts. The extract displayed dose-dependent cytotoxicity with an IC₅₀ of 140 μg/mL and reduced cell migration in HCT116 cells, indicating potential anti-proliferative effects. These findings suggest that T. siliquosa root extract, through synergistic phytochemical interactions, holds promise as a multi-targeted, plant-based therapeutic candidate for CDK4/6-associated cancers, warranting further in vitro and in vivo validation. Full article

Background: CDK4/6 inhibitor plus ET is a standard treatment for advanced HR+ BC. This study evaluates the efficacy and safety of CDK4/6 inhibitors with concurrent RT (SBRT and non-SBRT) in terms of pain, analgesic therapy changes, toxicities, and net clinical benefit (NCB). Methods: BC patients with bone metastases treated with RT and CDK4/6 inhibitor in the prospective observational COMBART study were analyzed. Pain was measured with the NRS. The NCB was defined by pain reduction (NRS), toxicity, and treatment changes. Adverse events (AEs) were graded per CTCAE v5.0. Statistical tests included chi-square and t-test. Results: Forty patients were treated with CDK4/6 inhibitor (palbociclib 30.8%, ribociclib 51.3%, abemaciclib 17.9%) and RT (131 lesions; 100 SBRT, 31 non-SBRT). The mean NRS score dropped from 3.52 (pre-treatment) to 1.31 (post-treatment) (p < 0.001), with better outcomes for patients treated with moderate hypofractionation (58.6% vs. 39.9% pain relief, p = 0.016). Pain relief was independent of the type of CDK4/6 inhibitor used (p = NS). Analgesic reduction was most common with palbociclib (35.4%, p = 0.001). Eight toxicities (grade 1–2) were reported. The NCB was 0.6 overall, higher with non-SBRT (0.74 vs. 0.52). Conclusions: RT plus CDK4/6 inhibitor, especially with moderate hypofractionation, significantly reduced pain with manageable toxicity. Analgesic therapy can often continue without stopping CDK4/6 inhibitor. Full article

Background: Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer frequently involves liver metastases, which are linked to poor outcomes. The optimal first-line treatment strategy in this subgroup remains unclear. Methods: This multicenter, retrospective study evaluated 121 patients with HR-positive, HER2-negative breast cancer and liver metastasis who had not received prior systemic chemotherapy or cyclin-dependent kinase (CDK) 4/6 inhibitors (e.g., palbociclib, ribociclib). Patients were classified based on their initial treatment during the liver metastatic phase (CDK4/6 inhibitors or chemotherapy). Clinical characteristics, treatment patterns, and survival outcomes were assessed. Cox regression analysis identified independent prognostic factors. Results: The median age was 53 years; 62% were postmenopausal. Chemotherapy was administered to 36.4%, and CDK4/6 inhibitors to 63.6% of patients. Most cases (59.5%) were recurrent disease. Baseline characteristics were comparable, except for the use of local liver-directed therapies. Progression-free survival favored CDK4/6 inhibitors (10.9 vs. 4.8 months; p < 0.01), while overall survival favored chemotherapy (42.2 vs. 25.9 months; p = 0.042). In multivariate analysis, initial treatment modality, local liver-directed therapy, hormonal status, and the size of the largest liver lesion were independent predictors of survival. Conclusions: In patients with HR-positive, HER2-negative breast cancer and liver metastasis, first-line chemotherapy was associated with improved overall survival compared to CDK4/6 inhibitors. Local liver-directed therapies contributed to longer survival, while larger liver lesions and endocrine-resistant disease correlated with worse outcomes. These findings support considering chemotherapy as first-line treatment in selected patients with aggressive liver metastatic disease. Full article

Background: Canine oral melanoma (COM) is an aggressive and often fatal neoplasm in dogs, with clinical and molecular similarities to human melanoma. Despite its relevance as a comparative oncology model, the molecular mechanisms underlying COM remain poorly understood. This study aimed to characterize gene expression profiles in COM to identify differentially expressed genes (DEGs), potential biomarkers, and therapeutic targets. Methods: In this pilot study, we performed RNA sequencing (RNA-seq) on tumor and healthy oral tissue samples from dogs. Two independent analytical pipelines—Bowtie2-DESeq2 and HISAT-StringTie-Ballgown—were used to ensure robustness in DEG detection. We also conducted pathway enrichment and isoform-level analyses to investigate biological processes and alternative splicing events. Results: Both approaches identified a core set of 929 common DEGs. Key oncogenic pathways, including MAPK/ERK and cell cycle regulation, were significantly affected, with notable upregulation of BRAF, NRAS, CDK4, and MITF (log2FC = 2.86, p < 0.001). The transcription factor SOX10 and the cytokine IL-33, both previously implicated in melanoma progression, were consistently overexpressed. Additionally, NF1, a known RAS pathway inhibitor, was also upregulated. Isoform analysis revealed novel transcript variants, suggesting a complex layer of post-transcriptional regulation in COM. Many DEGs remained uncharacterized, and chromosomal distribution analysis highlighted potential genomic influences. Conclusions: Our findings provide new insights into the molecular landscape of COM, reinforcing its utility as a model for human melanoma. The identification of conserved oncogenic pathways and novel transcript variants opens avenues for further functional studies and the development of targeted therapies in both veterinary and human oncology. Full article

Treatment with endocrine therapy (ET) in combination with CDK4/6 inhibitors has improved the outcome of patients with hormone receptor (HR)+/HER2- advanced breast cancer (ABC), but most patients eventually experience disease progression. Since the PI3K-AKT-mTOR (PAM), estrogen receptor (ER), and cyclin-dependent kinase (CDK) pathways are interdependent drivers of HR+/HER2- breast cancer (BC), the simultaneous inhibition of these pathways is expected to enhance anti-tumor control. Here we investigated the molecular and cellular effects of gedatolisib, a multi-target kinase inhibitor of the PAM pathway currently being evaluated in Phase 3 clinical trials, combined with fulvestrant and/or palbociclib in BC cell models. We found that the gedatolisib/fulvestrant/palbociclib triplet inhibited BC cell growth significantly more than the single agents or the palbociclib/fulvestrant doublet, both in vitro and vivo. Specifically, the triplet combination counteracted adaptive responses associated with single drug treatment, such as the reactivation of the CDK-RB-E2F pathway after palbociclib treatment, and inhibited multiple cellular functions, such as cell cycle progression, cell survival, protein synthesis, and glucose metabolism. The triplet combination was effective in treatment-naïve BC cell lines as well as in cell lines adapted to palbociclib and/or fulvestrant, regardless of PIK3CA/PTEN genetic alterations. Our findings provide a mechanistic rationale for conducting clinical studies evaluating gedatolisib in combination with CDK4/6 inhibitors and ET in HR+/HER2- ABC. Full article

Background: Tankyrase (TNKS1) regulates the WNT/β-catenin pathway, while CDK8 is a transcriptional regulator overexpressed in renal cell carcinoma (RCC). This study aims to identify novel dual inhibitors of tankyrase and Cyclin-dependent kinase 8 (CDK8), utilizing bioinformatics and in vitro methods and to assess their efficiency in renal cancer cells. Methods: To identify leads, the ChemBridge library was screening using high-throughput virtual screening (HTVS), which was followed by protein–ligand interaction analysis, Molecular Dynamics (MD) simulation, and Gibbs binding free energy estimation. A-498, Caki-1, and HK-2 cells were employed to validate in vitro efficacy. Results: TCS9725 was discovered by HTVS with binding affinities of −8.1 kcal/mol and −8.2 kcal/mol for TNKS1 and CDK8, respectively. TCS9725 had robust binding interactions with root mean square deviation values of 0.00 nm. The ΔG binding estimate was −27.45 for TNKS1 and −27.88 for CDK8, respectively. ADME predictions favored specific small-molecule inhibition profiles. TCS9725 reduced TNKS1 and CDK8 activities with IC50s of 243 nM and 403.6 nM, respectively. The compound efficiently inhibited the growth of A-498 and Caki-1 cells with GI50 values of 385.9 nM and 243.6 nM, respectively, with high selectivity compared to the non-cancerous kidney cells. TCS9725 decreased STAT1 and β-catenin positivity in A-498 and Caki-1 cells. The compound induced apoptosis and reduced TGFβ-stimulated trans-endothelial migration and p-smad2/3 signaling in both RCC cells. Conclusions: This work provides valuable insights into the therapeutic potential of TCS9725, a dual inhibitor of TNKS1 and CDK8. Further developments of this molecule could lead to new and effective treatments for this devastating disease. Full article