Search Results (422)

Background/Objectives: Capivasertib is a selective pan-AKT inhibitor recently approved in combination with fulvestrant for the treatment of hormone receptor-positive (HR+)/HER2- breast cancer with alterations in the PI3K/AKT pathway. The PI3K/AKT/mTOR signaling cascade represents a critical indication of endocrine resistance and tumor progression in this subtype of breast cancer. The present review summarizes current clinical data regarding the efficacy of capivasertib, either as monotherapy or in combination with other therapeutic agents and discusses emerging biomarkers and mechanisms of resistance. Methods: A literature search of the PubMed database was conducted to identify clinical trials evaluating capivasertib in breast cancer. Studies on capivasertib as monotherapy or in combination with fulvestrant, paclitaxel, or olaparib were included. Results: Findings from phase I–III clinical trials indicate that capivasertib in combination with fulvestrant significantly prolongs progression-free survival in patients with HR+/HER2- advanced breast cancer, particularly in tumors containing PIK3CA, AKT1, or PTEN alterations. Drug combination approaches with paclitaxel or olaparib have demonstrated additive or synergistic effects in triple-negative and DNA repair-deficient contexts, respectively. Monotherapy studies confirm effective pathway inhibition with modest clinical benefit, primarily in AKT1-mutant tumors. Translational analyses suggest that persistent mTORC1-mediated protein synthesis and compensatory signaling activation contribute to acquired resistance. Conclusions: Capivasertib constitutes a clinically validated therapeutic approach for the inhibition of AKT signaling in breast cancer. Its efficacy is most evident when combined with endocrine therapy; however, optimization of patient selection and rational combination strategies remains necessary to overcome resistance associated with mTORC1 activation and signaling redundancy. Full article

Despite extensive research, the treatment of ovarian cancer remains a significant challenge. One promising strategy involves the regulation of autophagy in cancer cells. However, this process is exceptionally complex and, depending on numerous factors, it can either suppress tumor progression, by maintaining genomic stability and limiting inflammatory responses, or exert a pro-tumor effect, enabling cancer cells to survive in unfavorable environmental conditions. Furthermore, the activation of this pathway can contribute to the development of resistance to drugs used in ovarian cancer therapy, such as cisplatin or paclitaxel. Current therapeutic approaches focus on both the induction and inhibition of autophagy, primarily by targeting the two most important pathways regulating this process: PI3K/Akt/mTOR and AMPK. Full article

Tumor Treating Fields (TTFields) represent a novel, non-invasive therapeutic modality in oncology that employs low-intensity, intermediate-frequency alternating electric fields to disrupt mitotic processes and induce cancer cell death. This review integrates mechanistic, preclinical, and emerging clinical evidence supporting the integration of TTFields with immunotherapeutic strategies in pancreatic ductal adenocarcinoma (PDAC). Although immunotherapy has transformed the treatment landscape across multiple malignancies, its efficacy in PDAC remains limited due to the tumor’s dense stroma, immunosuppressive microenvironment, and low immunogenicity. Preclinical investigations suggest that TTFields may potentiate immune-based therapies by enhancing antigen presentation, modulating the tumor microenvironment (TME), and attenuating mechanisms of immune resistance. We highlight studies evaluating TTFields in combination with immune checkpoint inhibitors (ICI), adoptive cellular therapies, and cancer vaccines, emphasizing their potential synergistic effects in PDAC. Clinically, the phase II PANOVA-2 trial demonstrated feasibility and encouraging survival outcomes with TTFields in combination with gemcitabine and nab-paclitaxel, providing the rationale for the ongoing phase III PANOVA-3 trial and the phase II PANOVA-4 trial, which combines TTFields with chemotherapy and atezolizumab. Additional clinical experiences in glioblastoma (GBM) and non-small-cell lung cancer (NSCLC) further substantiate the broader applicability of TTFields as an immunomodulatory adjunct. Remaining challenges include optimizing treatment sequencing, identifying predictive biomarkers, and managing TTFields-associated toxicities. Collectively, current evidence positions TTFields as a promising strategy to augment immunotherapy in PDAC, warranting further translational and clinical investigation to establish its role in reshaping therapeutic paradigms. Full article

Gastric cancer remains a highly heterogeneous malignancy in which chemotherapy response is limited by intrinsic and acquired resistance, cumulative toxicity, and the restricted predictive value of conventional preclinical models. This review critically synthesizes evidence on selected medicinal plants and their bioactive phytocompounds as adjuncts to standard chemotherapy for gastric cancer, with an emphasis on mechanistic plausibility, preclinical synergy, and translational barriers. Across the reviewed literature, phytocompounds from Curcuma longa, Scutellaria baicalensis, Camellia sinensis, Syzygium aromaticum, Glycyrrhiza glabra, Allium sativum, Marsdenia tenacissima, and Rhus verniciflua showed anticancer or chemopreventive activity through multitarget effects on apoptosis, proliferation, invasion, inflammation, oxidative stress, and resistance-associated signaling. The most convincing chemosensitizing evidence involved curcumin, wogonin, baicalein, EGCG, which enhanced the activity of fluoropyrimidines, platinum agents, paclitaxel, doxorubicin, or related antitumor regimens in selected gastric cancer models. However, the evidence base remains heterogeneous and is constrained by variable extract standardization, incomplete dose reporting, poor bioavailability, insufficient pharmacokinetic/pharmacodynamic integration, and underuse of clinically relevant model systems. Overall, medicinal plant bioactives remain promising adjunct candidates in gastric cancer. Still, meaningful translation will require chemically defined interventions, rigorous synergy analysis, interaction-aware study design, and validation in advanced preclinical and clinical settings. Full article

Macrophages are highly plastic cells of the tumor microenvironment, and although classically activated M1 macrophages are generally regarded as anti-tumor effectors, their prolonged cytotoxic activity may also promote tumor adaptation. In this study, we investigated whether sustained exposure of prostate cancer cells to cytotoxic M1-like macrophages results in the selection of tumor cell populations with enhanced malignant properties. Macrophage-resistant derivatives of the human prostate cancer cell lines PC3 and DU145 were generated by repeated co-culture with cytotoxic THP-1-derived macrophages and characterized in vitro and in vivo. Macrophage-selected tumor cells showed increased proliferative activity and enhanced clonogenic survival. In vivo, these cells formed larger xenograft tumors with more aggressive histopathological features. At the same time, their migratory activity was not significantly increased, although they displayed partial epithelial–mesenchymal transition-like changes, including increased vimentin expression without a marked loss of epithelial markers. Transcriptomic profiling revealed coordinated inflammatory and adaptive reprogramming, characterized by the enrichment of cytokine- and immune-response pathways together with the suppression of metabolic and differentiation-associated programs. These changes were accompanied by the selective activation of p38 MAPK signaling, while sensitivity to paclitaxel remained unchanged. Taken together, the results indicate that macrophage cytotoxicity may act as a selective pressure promoting the emergence of inflammation-adapted tumor cell variants with increased malignant potential, supporting re-evaluation of the role of M1-like macrophages in tumor progression. Full article

Taxanes, such as paclitaxel and docetaxel, are microtubule-stabilizing agents widely used in oncology, either as monotherapy or in combination regimens. While highly effective, these first-generation taxanes face important limitations, including significant toxicity, reduced water solubility, and the emergence of multidrug resistance. To address these challenges, semi-synthetic taxoids have been developed, aiming to improve pharmacological profiles and overcome therapeutic barriers. Central to these efforts is the understanding of structure-activity relationships, which guides the rational design of taxane analogues with enhanced efficacy and safety. This review explores recent advances in taxoid development, highlights findings from clinical trials, and evaluates how these new agents compare with traditional taxanes in terms of therapeutic potential and tolerability. While novel delivery systems offer improved outcomes with existing drugs, the development of new taxane analogues remains a promising approach to address drug resistance, albeit with challenges related to toxicity, high costs, and historically low success rates in drug development. Furthermore, taxanes are already used in certain cardiovascular conditions and show emerging potential in neurodegenerative diseases, although current evidence remains largely limited to preclinical or early-phase clinical studies. These developments mark an important evolution in the field and offer new opportunities for future therapeutic strategies. Full article

Glucosylceramide synthase (GCS) catalyzes ceramide glycosylation in response to cell stress that produces glucosylceramide and other glycosphingolipids. GCS overexpression is a cause of drug resistance and enriches cancer stem cells (CSCs) during cancer chemotherapy. Previous studies showed that GCS modulates the expression of p53 mutants and oncogenic gain-of-function (GOF) in heterozygous knock-in cell models (TP53 R273H^−/+). However, it is unclear whether GCS can modulate the effects of homozygous p53 mutations, which are common in many cancer cases. We report herewith that inhibition of GCS, via UGCG knockout and using an inhibitor (Genz-161), effectively re-sensitizes drug resistance and diminishes CSCs in colon cancer cells carrying the homozygous p53 R273H mutation. In aggressive WiDr cells carrying TP53 R273H mutation, knockout of UGCG gene using CRISPR/Cas9 editing or inhibition of GCS with Genz-161 sensitized cancer cells to oxaliplatin, irinotecan and paclitaxel. With decreased ceramide glycosylation in lipidomic profiling, both UGCG knockout and Genz-161 treatments substantially decreased wound healing, and diminished CSCs and tumor growth under chemotherapy. Interestingly, inhibition of RNA m⁶A methylation by neplanocin A markedly increased p53 function and reversed drug resistance. Mechanistic investigation revealed that GCS inhibition downregulated methyltransferase-like 3 (METTL3) expression and decreased RNA-m⁶A modification on mutant p53 R273H effects. Altogether, our findings demonstrate that ceramide glycosylation promotes METTL3 expression and RNA m⁶A methylation in response to drug-induced stress, thereby promoting mutant p53 expression and associated GOF. Conversely, inhibition of GCS can diminish CSCs and drug resistance via reduction in m⁶A modification and advance of p53-assocaited tumor suppressive function. GCS inhibition is an achievable approach for mutant cancer treatment. Full article

Triple-negative breast cancer (TNBC) tumors are typically heterogeneous, predominantly epithelial tissues with discrete patches of mesenchymal-like TNBC cells that differ in their invasiveness, proliferation potential and response to treatment. However, the impact of mesenchymal-like and epithelial TNBC cells on the persistence of chemotherapy-resistant disease remains poorly understood. Mesenchymal-like and epithelial TNBC cell types were detected by multiplex fluorescent immunohistochemistry using antibodies against vimentin, Ki67, and Annexin A6 (AnxA6). Chemotherapy drug-resistant mesenchymal-like and epithelial TNBC cell populations were established by pulse exposure and stepwise dose escalation and validated by 3D cultures and unbiased antibody arrays. Analysis of the response of TNBC tumors treated with six common chemotherapy regimens resulted in 36% complete response and 64% partial response with residual tumor sizes ranging from 0.5 to 37.0 mm. Treatment of TNBC cells with chemotherapy agents led to distinct resistance signatures including downregulation of survivin and upregulation of M-CSF and CXCL8/IL-8 in the model mesenchymal-like TNBC cells, and upregulation of CCL2/MCP-1, CTSS and DKK-1 in model epithelial TNBC cells. The inhibitory phosphorylation of GSK-3β (p-S9) increased in paclitaxel-resistant epithelial cells but decreased in resistant mesenchymal-like TNBC cells. Finally, chemotherapy resistance also activated p90 ribosomal S6 kinases (RSK1/2) in both cell types, while activation of mitogen- and stress-activated kinases (MSK1/2) was only observed in chemotherapy-resistant epithelial TNBC cells. These data reveal that chemotherapy resistance of epithelial and mesenchymal-like TNBC cellular subsets led to distinct profiles of proinflammatory and immune cell chemotactic cytokines and modulated the activities of GSK-3β, p90 RSK1/2 and the related MSK1/2. Targeting these factors and/or the associated signaling pathways may help overcome chemotherapy resistance in TNBC. Full article

A wide range of Leishmania species, transmitted by phlebotomine, cause leishmaniasis, which presents diverse clinical manifestations. Leishmaniasis has a high impact on vulnerable communities, primarily affecting people suffering from malnutrition or poor housing. Because leishmaniasis is associated with poverty, access to treatment is limited. In addition, high drug toxicity and therapeutic failure, related to drug resistance, remain major challenges. Therefore, there is a need to develop new therapeutic approaches that are safer and more effective. Drug combinations and repurposing are two strategies used in the development of treatments. The combination of drugs with different mechanisms of action can minimise resistance and allow dose reduction, increasing the likelihood of successful drug repurposing. This study evaluated the antileishmanial effects of combining antitumoral agents (paclitaxel and docetaxel) with standard drugs (miltefosine and paromomycin). Results demonstrated synergistic effects at higher doses. Furthermore, the antitumoral compounds enhanced the host immune response by promoting macrophage polarisation toward the M1 phenotype, essential for parasite control. These findings highlight a promising approach that could improve efficacy and reduce resistance. Full article

Advanced-stage ovarian cancer remains a major clinical challenge because of its aggressive behavior and the frequent development of chemoresistance. The nuclear factor erythroid-derived 2–like 2 (NRF2) signaling pathway regulates cellular redox homeostasis. However, its role in ovarian cancer stem-like cells remains unclear. Therefore, we aimed to investigate the effects of NRF2 overexpression on acetaldehyde dehydrogenase (ALDH)⁺ KURAMOCHI ovarian cancer cells in vitro and in vivo. In particular, we investigated the effects of NRF2 on tumor-associated behaviors, chemoresistance, and signaling pathways. Lentivirus-mediated NRF2 overexpression activated extracellular signal-regulated kinase and AKT signaling. Moreover, it modulated tumor-associated phenotypes, including proliferation, migration, and invasion. NRF2-overexpressing cells exhibited significantly enhanced migratory and invasive capacities, increased resistance to paclitaxel and carboplatin, and reduced apoptosis. Furthermore, the expression of anti-apoptotic proteins was upregulated, and caspase-3 activation was attenuated. In xenograft models, NRF2 overexpression promoted tumor growth and increased the expression of antioxidant and angiogenic factors, including heme oxygenase-1 and vascular endothelial growth factor A. Collectively, these findings demonstrate that NRF2 regulates ovarian cancer aggressiveness and chemoresistance by coordinating stress response signaling, survival pathways, and tumor progression. Therefore, targeting NRF2-mediated signaling represents a promising therapeutic strategy for overcoming drug resistance and improving outcomes in patients with ovarian cancer. Full article

Background: Co-delivery of two drugs with diverse physicochemical properties and a specific administration sequence holds great importance in cancer theranostics to overcome drug resistance and reduce side effects. Paclitaxel (PTX) and hydroxycamptothecin (HCPT) have long been used clinically as chemotherapeutic agents for Nasopharyn-geal carcinoma (NPC). However, their clinical application is severely restricted by low water solubility, poor stability, and systemic adverse reactions. Nanoparticle-based drug delivery systems provide a promising platform for combination cancer therapy. Methods: In this study, folic acid-modified and dual drug-loaded self-assembled HCPT/PTX@FA@p-PS-SPIONs were successfully fabricated via the emulsification–solvent evaporation method using amphiphilic phosphorylated polystyrene (p-PS). The characterization, cellular uptake, and in vivo pharmacokinetic profiles of the nanoparticles in NPC models were systematically investigated. Result: HCPT/PTX@FA@p-PS-SPIONs were successfully prepared with p-PS as the copolymer backbone. The nanoparticles exhibited a uniform particle size of 196.9 ± 5.5 nm and a zeta potential of −7.3 ± 0.7 mV. The encapsulation efficiency (EE) was 81.4 ± 2.5% for PTX and 67.6 ± 4.1% for HCPT. The drug loading (DL) efficiency was 18.4 ± 1.5% for PTX and 12.2 ± 1.0% for HCPT. HCPT/PTX@FA@p-PS-SPIONs showed favorable biocompatibility. Sustained and sequential release of the two drugs contributed to an enhanced therapeutic effect. Moreover, under magnetic field (MF) guidance, HCPT/PTX@FA@p-PS-SPIONs exhibited stronger inhibitory effects on NPC cells than single-drug, cocktail, or dual-drug groups, demonstrating the superiority of the combined therapy. Pharmacokinetic studies in rats revealed that the half-lives of PTX and HCPT were 3.9 ± 1.2 h and 4.7 ± 1.1 h, respectively, confirming that HCPT/PTX@FA@p-PS-SPIONs could resist rapid metabolism and clearance in vivo. Conclusions: The long-circulating, folic acid-targeted nanoparticles HCPT/PTX@FA@p-PS-SPIONs show great potential for the targeted therapy of nasopharyngeal carcinoma. Full article

Ovarian cancer is a devastating disease that is often diagnosed in the late stages. The typical therapeutic approach includes surgery plus cytotoxic drugs such as carboplatin and paclitaxel. In recent years, the advent of poly ADP-ribose polymerase (PARP) inhibitors such as olaparib has offered additional treatment opportunities for patients with BRCA mutations or homologous recombination deficiencies. Nevertheless, resistance to therapy usually occurs, leading to poor overall survival. Therefore, novel treatments are needed for this disease. One of the obstacles to successful treatment is the highly immunosuppressive nature of the ovarian cancer microenvironment. Recent strategies for the treatment of ovarian cancer and other types of cancer involve targeting the metabolism of cancer cells and other cells of the tumor microenvironment. One drug that has been investigated both in preclinical studies and clinical trials as an antitumor agent is metformin. This drug, typically used for the treatment of type-2 diabetes for its capability to lower blood glucose, can directly affect cancer cell growth and survival by activating the AMPK (adenosine monophosphate-activated protein kinase) pathway. Furthermore, it can affect the phenotype of other cells of the tumor microenvironment such as macrophages and T cells. In this review, we summarize the main characteristics of ovarian cancer and describe preclinical studies and clinical trials involving metformin as a therapeutic agent for this disease. Full article

The glioma tumor microenvironment (TME) exhibits profound heterogeneity that drives tumor progression and therapy resistance. By integrating single-cell RNA sequencing (eleven samples) and spatial transcriptomics (two samples), the cellular components of the glioma microenvironment were deconvoluted, revealing tumor-associated foam cells (TAFCs) as the most abundant and centrally connected subtype. The high expression of two prognostic candidate genes, growth differentiation factor 8 (GDF-8, also known as myostatin, MSTN) and transcription factor 12 (TCF12), in TAFCs was found to be correlated with poor overall survival. These two genes were associated with M2 macrophage infiltration, altered cholesterol homeostasis, and immunosuppressive signaling. Regulatory network and pathway analyses, based on computational motif enrichment and co-expression analysis, linked them to ribosome, Notch signaling, DNA repair, and cell-cycle pathways. Pseudotime trajectories revealed dynamic expression during differentiation. Additionally, drug sensitivity prediction analysis demonstrated that MSTN expression was significantly associated with sensitivity to paclitaxel and VE-822, while TCF12 expression showed potential associations with sensitivity to cytarabine, olaparib, Wee1 inhibitor, paclitaxel, and VE-822. Logistic regression analysis combining clinical parameters with MSTN and TCF12 expression effectively achieved risk stratification for glioma, with higher composite scores predicting worse 2- and 3-year survival outcomes. Calibration curves demonstrated high consistency between nomogram-predicted overall survival probabilities and actual observed outcomes. Immunofluorescence confirmed upregulated expression of MSTN and TCF12 in glioma tissues and their co-localization with macrophages. In conclusion, this study identified TAFCs as the central cells in the glioma microenvironment, with their signature genes MSTN and TCF12 representing candidate immunometabolic signatures associated with macrophage-mediated immunosuppression and metabolic reprogramming in glioma, suggesting their potential as biomarkers for patient stratification and as targets for immunometabolic therapies. Full article

Background. NOTCH receptors play a pivotal role in carcinogenesis. Upon ligand binding, a cascade of proteolytic cleavages mediated by ADAM proteases and the γ-secretase complex activates the receptor, ultimately releasing the NOTCH intracellular domain (NICD). NICD translocates to the nucleus, where it regulates gene expression. This review mainly aims to evaluate γ-secretase inhibitors (GSIs) as anticancer agents in preclinical and clinical settings, with a focus on their ability to block tumor progression, target cancer stem cells, and overcome resistance to standard therapies. Methods. A systematic search was conducted in the ISI Web of Science, PubMed, and Scopus databases, following PRISMA guidelines. The review included preclinical in vitro and in vivo studies, as well as clinical trials, investigating GSIs, either as monotherapy or in combination with other treatments, in TNBC, metastatic melanoma, PDAC, gastric cancer, and NSCLC. Exclusion criteria included duplicates, non-English articles, studies published before 2010, studies on non-cancer conditions, research unrelated to NOTCH signaling, and studies outside the selected cancer types. Overall, 69 articles were included and categorized into the five types of cancer analyzed (20 on NSCLC, 22 on TNBC, 11 on metastatic melanoma, 7 on GC, and 9 on PDAC). Of these, 60 studies corresponded to preclinical research in the types of cancer, and 9 studies corresponded to clinical trials in the types of cancer except for GC. Two independent authors screened and extracted relevant data, with disagreements resolved by the corresponding author. Findings were synthesized qualitatively across cancer types under study. Results. This review summarizes therapeutic advances involving GSIs in cancers driven by oncogenic NOTCH signaling, based on the 69 articles included. Preclinical studies show that GSIs synergize with chemotherapy and radiotherapy, particularly in NSCLC, melanoma, and TNBC, and block EMT, overcome therapeutic resistance, and improve prognosis. Commonly used GSIs include DAPT and RO4929097, which enhance the efficacy of agents, such as gemcitabine (PDAC), paclitaxel, osimertinib, erlotinib, and crizotinib (NSCLC), and 5-FU (gastric cancer, TNBC). Promising strategies include combining GSIs with SAHA, ATRA, CB-103, and other NOTCH signaling targeting molecules, either alone or with chemo- and radiotherapy. Clinical trials with GSIs, however, remain limited. RO4929097 is the most extensively tested GSI in clinical settings. PDAC trials combining GSIs with gemcitabine showed no benefit; melanoma trials yielded modest outcomes; and TNBC trials demonstrated partial responses to GSIs but overall low efficacy and significant adverse events. Discussion and Conclusions. Despite encouraging preclinical evidence, clinical trials with GSIs have underperformed, largely due to tumor heterogeneity, dosing limitations, and the non-selective nature of γ-secretase inhibition. Other NOTCH inhibitors, such as DLL4 antibodies, also resulted in partial responses and secondary effects. Future strategies should prioritize receptor-specific NOTCH inhibitors, patient stratification based on NOTCH pathway activation, and optimized combination regimens. Emerging approaches include integrating immunotherapy with advanced technologies such as CRISPR, CAR-T cells, and bispecific antibodies, as well as targeted delivery systems to enhance efficacy and reduce toxicity. Additional research directions include addressing the tumor microenvironment and EMT-driven resistance, elucidating the mechanisms of immune evasion, and inhibiting tumor angiogenesis. Finally, leveraging artificial intelligence and big-data-driven personalized medicine, including sex-specific considerations, will be essential for improving patient outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune cell dysfunction and poor prognosis. CD44, a cell surface glycoprotein with multiple splice variants, has been implicated in tumor progression, but its compartment-specific roles in PDAC remain unclear. CD44 standard and variant isoform expression was analyzed in patient-derived lymph nodes (LNs) by quantitative PCR. Immune cell-specific CD44 expression was assessed by flow cytometry in LNs and peripheral blood. Soluble and exosome-associated CD44 (exo-CD44) were measured in plasma. Clinical associations and survival analyses were performed. Transcriptomic, immune infiltration, immune checkpoint, and drug sensitivity analyses were conducted using TCGA-PAAD and pharmacogenomic datasets. CD44 standard isoform expression was unchanged in PDAC LNs, whereas multiple CD44 variant isoforms (v4–v10) were significantly reduced and associated with metastatic disease and poor survival, particularly CD44v5, v6, v7, and v10. CD44 expression was enriched in CD45⁺ immune cells, with highest levels in CD4⁺ T cells in both LNs and blood. Soluble CD44 levels showed no clinical associations. In contrast, exo-CD44 levels were reduced overall in PDAC but increased in patients with distant metastasis, positive resection margins, systemic inflammation, and reduced survival. High CD44 expression was associated with advanced disease, immune cell infiltration, immune checkpoint gene expression, reduced sensitivity to gemcitabine, paclitaxel, rapamycin, and FMK, and distinct CTLA4/PD-L1 checkpoint profiles. CD44 exhibits compartment-specific regulation in PDAC, linking immune remodeling, exosome signaling, and therapeutic resistance to adverse clinical outcome. Full article