Search Results (1,592)

Acute Myeloid Leukemia (AML) is a genetically and clinically heterogeneous malignancy marked by poor prognosis and limited therapeutic options, especially in older patients. While conventional treatments such as the “7 + 3” chemotherapy regimen and allogeneic stem cell transplantation remain standard care options, the advent of next-generation sequencing (NGS) has transformed our understanding of AML’s molecular complexity. Among the emerging hallmarks of AML, metabolic reprogramming has gained increasing attention for its role in supporting leukemic cell proliferation, survival, and therapy resistance. Distinct AML subtypes—shaped by specific genetic alterations, including FLT3, NPM1, and IDH mutations—exhibit unique metabolic phenotypes that reflect their underlying molecular landscapes. Notably, FLT3-ITD mutations are associated with enhanced reactive oxygen species (ROS) production and altered energy metabolism, contributing to disease aggressiveness and poor clinical outcomes. This review highlights the interplay between metabolic plasticity and genetic heterogeneity in AML, with a particular focus on FLT3-driven metabolic rewiring. We discuss recent insights into how these metabolic dependencies may be exploited therapeutically, offering a rationale for the development of metabolism-targeted strategies in the treatment of FLT3-mutated AML. Full article

Metastasis is the main cause of failure in anticancer therapies, and is frequently related to poor prognosis for patients. The true challenge in extending cancer patient life expectancy, eventually managing cancer as a chronic disease with periodic but controllable relapses, relies on the development of effective therapeutic strategies specifically targeting key mechanisms involved in the metastatic cascade. Traditional chemotherapy with alkylating agents, microtubule inhibitors, and antimetabolites has shown limited efficacy against metastatic cells, largely due to the emergence of chemoresistant populations that undergo epithelial-to-mesenchymal transition (EMT), promoting the colonization of distant organs and sustaining metastatic progression. This scenario has spurred significant efforts to identify small molecules and biologics capable of interfering with specific steps in the metastatic process. In this review, we provide an overview of recent advances involving small interfering RNAs (siRNAs) and microRNAs (miRNAs) in cancer therapy. Although most of these agents are still under investigation and have not yet been approved for clinical use, insights into their development stage offer valuable information to identify new targets in the ongoing fight against metastasis. Particular emphasis is placed on the role of chemical modifications applied to siRNAs, such as backbone, sugar, terminal, base, and conjugation changes, and how these factors influence their stability, immunogenicity, and targeting precision. By integrating these aspects into the discussion, this review provides a focused and up-to-date resource for researchers in medicinal chemistry, drug delivery, and pharmaceutical formulation, where molecular design plays a critical role in therapeutic success. Full article

Malignant bone and soft tissue tumors are often resistant to conventional treatment, and treatment options for unresectable and metastatic cases are limited. L-type amino acid transporter 1 (LAT1) is overexpressed in several malignancies, including sarcomas, making it an attractive target for targeted alpha therapy. In this study, we investigated the therapeutic efficacy of LAT1-targeted alpha therapy using a novel modified 3-astatin-211 Astato-α-methyl-L-tyrosine (²¹¹At-AAMT) for bone and soft tissue sarcomas. LAT1 expression and the specificity of LAT1-mediated uptake of ²¹¹At-AAMT were evaluated in bone and soft tissue sarcoma cell lines. Antiproliferative effects were assessed using cell viability and colony formation assays. DNA damage was assessed using immunostaining with phosphorylated histone γH2AX. In vivo efficacy of ²¹¹At-AAMT, determined using xenograft mouse models, was compared with that of doxorubicin. LAT1 was highly expressed in all cell lines, especially MP-CCS-SY and MG-63 cells. ²¹¹At-AAMT uptake was LAT1-dependent and significant in all cell lines. It inhibited cell proliferation in a dose-dependent manner, comparable to that of doxorubicin. In xenograft models, a single administration of ²¹¹At-AAMT significantly inhibited tumor growth without systemic toxicity, whereas doxorubicin caused weight loss. Histopathological analysis showed reduced cell density, inhibited proliferation, and extensive DNA damage in tumors treated with ²¹¹At-AAMT, whereas LAT1 expression was maintained in residual tumor tissues. LAT1-targeted alpha therapy with ²¹¹At-AAMT demonstrated antitumor efficacy comparable to that of first-line chemotherapy for osteosarcoma and soft tissue sarcoma. Sustained LAT1 expression suggests the potential for repeated or combination treatments, highlighting its promise as a novel therapy for advanced, treatment-resistant sarcomas. Full article

Objective: Sinonasal squamous cell carcinoma (SNSCC) is a rare and aggressive malignancy, with limited treatment strategies in the recurrent or metastatic cases. Although immune checkpoint inhibitors (ICIs) have shown efficacy in head and neck cancers (HNCs), clinical data specific to SNSCC are scarce. This study aimed to evaluate the therapeutic efficacy and prognosis of ICIs in patients with SNSCC. Methods: We conducted a retrospective review of 18 patients with pathologically confirmed SNSCC treated with nivolumab or pembrolizumab at Gifu University Hospital between May 2017 and December 2024. Treatment response was assessed using RECIST v1.1 criteria. Overall response rate (ORR) and disease control rate (DCR) were evaluated as treatment effects, and overall survival (OS) and progression-free survival (PFS) were evaluated as prognoses. Subgroup analyses were performed according to treatment regimen. Results: The ORR and DCR for all patients were 43.8% and 56.3%, respectively. Pembrolizumab-treated patients showed higher response rates (ORR: 66.7%; DCR: 83.3%) compared to those treated with nivolumab (ORR: 30%; DCR: 40%). Median OS and PFS were 21.5 and 7.9 months, respectively. Long-term durable responses exceeding two years were observed in several cases. Although pembrolizumab tended to result in better outcomes, no statistically significant difference was found between groups. Immune-related adverse events were infrequent and manageable. Conclusions: This study suggests that a subset of patients with SNSCC may benefit from ICI therapy, particularly in combination with chemotherapy. Despite the rarity of SNSCC, accumulating clinical evidence—including prospective studies—is essential to establish standardized treatment strategies for this disease. Full article

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, often diagnosed at an advanced stage due to its asymptomatic progression. The high recurrence rate and development of platinum-based chemotherapy resistance contribute to its poor prognosis. Despite advancements in molecular profiling, predictive biomarkers for chemotherapy response and recurrence risk remain limited. In this study, we developed OvarianTag™, a biomarker panel integrating apoptosis and necroptosis pathways, to predict chemotherapy benefit and disease progression in EOC patients. This observational study was conducted in two phases. In the first phase, 45 patients were recruited, and RNA was extracted from fresh ovarian tissues (normal, benign, and malignant). qRT-PCR was performed to assess the relative expression of genes involved in apoptosis and necroptosis-regulated cell death pathways. Machine learning algorithms were applied to identify the relevant prognostic markers, leading to the development of OvarianTag™. In the second phase, 55 additional EOC patients were included, and their formalin-fixed, paraffin-embedded (FFPE) tumor samples were analyzed using qRT-PCR. The classifier algorithm incorporated hierarchical clustering to stratify patients based on gene expression profiles. Significant differences in TNFRSF10C/TRAIL-R3, TNFRSF10B/TRAIL-R2, and CASP8 expression levels were observed between patient groups. CASP8 downregulation was strongly correlated with platinum resistance and a poor prognosis. Decision tree models achieved 83.3% accuracy in predicting platinum response and 79.2% accuracy in recurrence risk stratification. The OvarianTag™ classifier demonstrated high sensitivity and specificity in identifying high-risk patients, supporting its potential as a prognostic tool. The OvarianTag™ panel provides a novel approach for risk stratification in EOC, integrating apoptosis and necroptosis pathways to refine chemotherapy response prediction and recurrence risk assessment. This molecular assay has the potential to guide personalized treatment strategies, enhancing clinical decision-making and improving patient outcomes. Further validation in independent cohorts is warranted to establish its clinical utility. Full article

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with pediatric ALL having a ~90 percent cure rate, while the adult cure rate is considerably lower. B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of ALL and is generally treated through a variety of chemotherapy drugs that can cause undesired side effects, adverse events, or other complications. Consequently, there is a need for improved understanding of the shared gene expression profiles and underlying molecular mechanisms shared among various B-ALL subtypes. In this study, 259 publicly available RNA-sequencing samples were evaluated and retrieved from the NCBI Gene Expression Omnibus (GEO) database and then pre-processed using a robust computational workflow. Differential gene expression, pathway enrichment, marker prediction, and drug repurposing analyses were then performed to facilitate a better mechanistic understanding of disease. We found both previously identified as well as novel differentially expressed genes. Specifically, we observed upregulation in the HIST2H2AA3, EPHA7, and MPR1 genes; while downregulation was observed for the IGHA1, ANGPTL1, and CHAD genes. We identified multiple pathways, including “Integrins in Angiogenesis”, to be significantly affected in B-ALL. We then used these significant pathways to predict and rank 306 existing therapeutic targets that could potentially be repurposed for B-ALL, including three that have not been evaluated in human clinical trials. Using a tree-based classification algorithm, we also predicted ADAM28 as a possible mechanistic marker. The results of this study have potential implications for patients who have been diagnosed with B-ALL by providing improved mechanistic understanding and information on possible diagnostics and repurposed therapeutics for B-ALL. Full article

A growing body of evidence confirms that non-mutational epigenetic reprogramming constitutes an important hallmark of cancer, contributing to the heterogeneity and phenotypic plasticity observed in cancers. Among the many epigenetic modulators, histone lysine demethylases (KDMs) have emerged as promising targets for pharmacological inhibition in cancer treatment. KDMs were found to be frequently overexpressed and/or hyperactivated in cancer cells, and their inhibition was shown to result in the inhibition of cancer cell growth both in vitro and in vivo. The inhibition of Lysine-specific histone demethylase 1A (LSD1), KDM3, KDM4, KDM5, and KDM6 may affect cell survival, proliferation, motility, and apoptosis induction. Importantly, KDM inhibitors can be used as modulators of anti-cancer immune response and sensitivity to radiation and chemotherapy. This narrative review aims to present the most recent evidence documenting the anti-cancer potential of KDM inhibitors. Full article

Acute myeloid leukemia (AML) proliferation is significantly influenced by the interactions between leukemia blasts and the bone marrow (BM) microenvironment. Specifically, bone marrow mesenchymal stem cells (BMSCs) derived from AML patients (AML-MSCs) are known to support leukemia growth and facilitate disease progression. Studies have demonstrated that the transfer of mitochondria from MSCs to AML blasts not only aids in disease progression but also contributes to chemotherapy resistance. Furthermore, BM stromal cells can trigger a metabolic shift in malignant cells from mitochondrial respiration to glycolysis, which enhances both growth and chemo-resistance. This study focuses on identifying transcriptional and metabolic alterations in AML-MSCs to uncover potential targeted therapies for AML. We employed RNA sequencing and microarray analysis on MSCs cocultured with leukemic cells (MLL-AF9) and on MSCs isolated from both non-leukemic and MLL-AF9 leukemic mice. The Gene Set Enrichment Analysis (GSEA) indicated a significant downregulation of gene sets associated with oxidative phosphorylation and glycolysis in AML-MSCs. Furthermore, coculture of MSCs from wild-type mice (WT-MSCs) and a healthy donor individual (HD-MSCs) with AML cells demonstrated reduced oxidative phosphorylation and glycolysis. These metabolic changes were consistent in AML-MSCs derived from both leukemic mice and patients. Our results indicate that AML cells diminish the metabolic capacity of MSCs, specifically targeting oxidative phosphorylation and glycolysis. These findings suggest potential metabolic vulnerabilities that could be exploited to develop more effective therapeutic strategies for AML. Full article

Background: Primary lymphoma of peripheral nerves (PLPN) is a rare extranodal non-Hodgkin lymphoma that mimics benign nerve conditions, leading to diagnostic delays. This systematic review evaluates the clinical, radiological, and pathological features of PLPN, alongside diagnostic and therapeutic strategies. Materials and Methods: A systematic search was conducted across PubMed, Scopus, and Web of Science, and identified 23 studies reporting 27 cases of PLPN. Data on demographics, clinical presentation, diagnostics, treatment, and outcomes were extracted and synthesized qualitatively due to study heterogeneity. Results: The sciatic nerve was most involved (48.15%), followed by the ulnar (18.5%) and radial nerves (18.5%). The median age at diagnosis was 58 years, with symptoms including motor deficits (88.9%), sensory disturbances (74.1%), and pain (70.4%). B-cell lymphomas accounted for 81.5% of cases, predominantly diffuse large B-cell lymphoma. MRI findings were non-specific; however, diffusion-weighted imaging (DWI) showed diagnostic potential. Treatments included combination therapies (51.9%), chemotherapy (25.9%), and surgery. Complete remission was achieved in 70.8%, with a 2-year survival rate of 83.3%. Conclusions: PLPN is rare but likely underdiagnosed. Early recognition requires multidisciplinary collaboration, advanced imaging, and standardized protocols. Future research should focus on molecular characterization, diagnostic criteria, and treatment optimization to improve outcomes for this challenging condition. Full article

In vitro culture systems have advanced cancer biology, particularly through 2D and 3D tumor cultures. These have answered numerous scientific inquiries and propelled human oncologic research, with growing recognition of their potential to improve cancer treatment in companion animals, specifically cats and dogs. These species develop cancer spontaneously, closely resembling specific human cancer subtypes. For example, canine and feline mammary tumors are especially valuable for studying tumor biology. In vitro models from these tumors therefore offer a unique opportunity for veterinary cancer research. Recent 3D cell culture advancements provide promising platforms for predicting therapeutic responses in human cancer and may be applied to mammary tumors in animals. However, while limitations in fully recapitulating in vivo conditions and predicting chemotherapy response have been observed in colorectal tumoroids, similar challenges are emerging in mammary and breast tumors. In particular, canine mammary tumors and human breast cancers share critical heterogeneity and microenvironmental factors usually inadequately modeled in vitro. This review critically examines the predictivity of 3D mammary tumoroids from humans and companion animals, highlighting challenges related to stromal and immune cell preservation, reproducibility, and the translational gap between in vitro findings and clinical outcomes. We propose future directions to optimize these models for both comparative oncology and veterinary-specific applications. Full article

The L1 molecule is a cell adhesion molecule (L1CAM) that was originally implicated in neuronal development. In recent years, studies of several large cohorts of patients with endometrial cancer have revealed that L1CAM acts as a poor prognostic factor, in most cases independent of other parameters. It seems to be an important factor, especially in the non-specific molecular profile subgroup (p53 normal expression, MMR proficient, POLE not mutated) of endometrial cancer, and a factor predictive of the response to chemotherapy. This review aims to gather most of the current knowledge regarding this promising prognostic factor. Full article

Background: Pancreatic cancer ranks as the fourth leading cause of cancer-related deaths in the USA. The human aldehyde dehydrogenase (ALDH) family comprises 19 functional members and has been implicated in prognosis and therapy resistance. However, it remains unclear which specific ALDHs are associated with adverse prognoses in pancreatic cancer. Methods: We obtained transcriptomic and clinical data for pancreatic adenocarcinoma (PAAD) from the TCGA, corresponding mutational data, and normal pancreatic tissue transcriptomic data from GTEx. Prognostic analysis was carried out using Kaplan–Meier analysis. KEGG and GO analyses were used for biological signaling pathways, and ESTIMATE algorithms were used for tumor microenvironment (TME) assessment. CIBERSORT algorithm, immune infiltration analysis, and OncoPredict algorithms were employed for predicting chemotherapy sensitivity. Results: Our study identified four of the 19 ALDH genes (ALDH1L1, ALDH3A1, ALDH3B1, ALDH5A1) that were significantly associated with pancreatic cancer prognosis. High expression of ALDH1L1, ALDH3A1, and ALDH3B1 was associated with shorter overall survival, while ALDH5A1 expression was associated with longer overall survival of pancreatic cancer patients. Clinicopathological analysis revealed a significant association with KRAS mutational status and ALDH3A1 expression. Immune correlation analysis indicated that high expression of ALDH3A1 and ALDH3B1 was associated with lower expression of CD8⁺ T cell-associated gene expression. ESTIMATE analyses further revealed that high expression of ALDH3A1 and ALDH3B1 was associated with lower levels of immune cell infiltration. PAAD tumors with low ALDH3A1 expression were more sensitive to paclitaxel. Immunohistochemical analysis demonstrated high expression of ALDH3A1 in pancreatic cancer cells of human tumor tissues compared to normal pancreatic tissues. Conclusions: This study unveils specific ALDH family members relevant for prognosis and chemotherapy response in pancreatic cancer patients. These findings contribute valuable insights into prognostic biomarkers and their potential clinical utility in the treatment of pancreatic adenocarcinoma. Full article

Research into aggressive gynecologic cancers such as uterine serous carcinoma (USC) has recently evolved from chemotherapy to the development of drugs targeting specific biomarkers differentially expressed/active in tumor cells. One such target is HER2/neu, which plays an important role in the coordination of cell growth and differentiation. Importantly, when overexpressed and/or amplified in tumor cells, the downstream tyrosine kinase of HER2/neu becomes constitutively activated, causing dysregulated gene transcription. In breast cancer patients, HER2/neu has been successfully utilized for many years as a target for multiple monoclonal antibodies and more recently antibody–drug conjugates (ADCs). Use in gynecologic malignancies has been slower, however, due to recently identified unique characteristics of HER2/neu protein expression and gene amplification in biologically aggressive tumors such as USC including its major heterogeneity and lack of apical staining when compared to breast cancer. Accordingly, the use of optimal testing algorithms for HER2/neu status in patients with USC may have important implications for the development of novel, effective, and targeted treatment modalities against this lethal variant of endometrial cancer. In this review, we discuss HER2/neu gene expression in USC, evaluate the efficacy of HER2/neu-directed therapies in both preclinical and clinical settings, and discuss possible mechanisms of resistance to HER2/neu targeting agents. Full article

Background: Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy characterized by rapid growth, early metastatic dissemination, and a dismal prognosis. For decades, treatment paradigms remained largely stagnant, particularly for extensive-stage disease (ES-SCLC). However, the last five years have witnessed a significant evolution in the therapeutic landscape. Methods: The information for this article was gathered by synthesizing data from several key sources. This article synthesizes the evidence supporting current standards of care for both limited-stage (LS-SCLC) and ES-SCLC, incorporating data from pivotal clinical trials, a network meta-analysis of first-line chemoimmunotherapy regimens, and a critical appraisal of international treatment guidelines, and a critical analysis of international treatment guidelines from prominent organizations like the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO). This comprehensive approach allows for a robust and well-supported summary of the current therapeutic landscape. Results: For limited-stage SCLC (LS-SCLC), concurrent chemoradiotherapy (cCRT) remains the curative-intent standard, but its efficacy is now being augmented by consolidative immunotherapy, as demonstrated by the landmark ADRIATIC trial. The role of prophylactic cranial irradiation (PCI) in LS-SCLC is being re-evaluated in the era of high-sensitivity brain imaging and concerns over neurotoxicity. For ES-SCLC, the treatment paradigm has been fundamentally transformed by the integration of immune checkpoint inhibitors (ICIs) with platinum–etoposide chemotherapy, establishing a new standard of care that offers a modest but consistent survival benefit. Conclusions: The treatment of SCLC has been significantly advanced by the integration of immunotherapy, particularly for extensive-stage disease, which has established a new standard of care and improved patient outcomes. Looking to the future, the quest for predictive biomarkers and the development of novel therapeutic classes, such as Bi-specific T-cell Engagers (BiTEs) and antibody–drug conjugates, promise to build upon recent progress and offer new hope for improving the dismal prognosis associated with this disease. Full article

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a key regulator of cancer stem cell (CSC) biology and signaling. In CSCs, ROR1 acts as a receptor or co-receptor, interacting with non-canonical WNT ligands, and forming complexes with proteins like CD19 and HER2, to activate diverse downstream signaling pathways. ROR1 signaling in CSCs promotes proliferation, maintains stemness, and enhances migration, invasion, and the epithelial-to-mesenchymal transition (EMT). While minimally expressed after embryogenesis, ROR1 is aberrantly upregulated in numerous cancers, including ovarian, breast, pancreatic, and hematologic malignancies. ROR1 overexpression drives tumor progression, resistance to chemotherapies, disease recurrence, and ultimately metastasis. This expression pattern positions ROR1 as a promising target for CSC-specific therapies. High ROR1 expression is consistently linked to aggressive disease and poor patient outcomes. Here, we review ROR1′s role in CSCs and highlight the complex signaling that is observed in the CSC population. Further, we evaluate the gaps in the current understanding of ROR1 signaling in CSCs and describe how ROR1 regulates the associated signaling pathways. Finally, we provide an up-to-date summary of the promising therapeutic strategies targeting ROR1 that overcome conventional cancer treatment limitations. This review highlights the role of ROR1 as a critical, functional driver of CSCs and adverse patient outcomes across various malignancies. Full article