Search Results (15,785)

Background: Gynecological cancers include collections of cancers with diverse cellular and molecular characteristics that often develop drug resistance, making them treatment-resistant. Biomolecule–drug conjugates (BDCs), especially antibody–drug conjugates (ADCs), have revolutionized the targeted therapy of cancer; however, the creation of these entities has so far been achieved by empirical, resource-intensive design methods. Objective: The aim of this review is to critically analyze how AI can be used for the rational design and optimization of high-affinity BDCs for gynecological cancer treatment. Methods and discussion: Recent advances in machine learning (ML)- and deep learning (DL)-based methods to predict biomolecule-target binding affinity, structural compatibility, linker stability, payload selection, trafficking in the cell, and biomolecule resistance mechanisms are summarized. The review also explores the possibilities for incorporation of structural, chemical, biological, and multi-omics data to enhance specificity, efficacy, and safety of conjugates. Besides antibody-based systems, AI-assisted design approaches with peptides, aptamers, and hybrid biomolecular systems are also included. This review also highlights parameters and experimental/numerical validation restrictions related to data quality, interpretability of models, regulatory aspects, etc. Conclusions: AI-based conjugate engineering is increasingly moving BDC development from a largely ‘trial and error’ approach to a more predictive and data-driven approach. While there are still challenges to be addressed in terms of translations and validations, the potential of AI approaches in the field of precision oncology and the development of more personalized treatment is promising in the context of gynecological cancers. Full article

The prioritization of biomarkers that inform molecular-targeted cancer research remains challenging because tumor vulnerabilities are context-dependent. The ubiquitin–proteasome system is essential for cancer cell survival; however, the functional and biomarker-level relevance of individual proteasome subunits has not been systematically defined across cancer types. In this study, we performed an integrative pan-cancer analysis to prioritize proteasome subunits that function as context-dependent vulnerability biomarkers. We analyzed proteasome subunits and proteasome-associated genes across 54 cancer types by integrating large-scale CRISPR (n = 1178 cell lines) and RNAi (n = 707 cell lines) dependency datasets with transcriptomic, survival, immune infiltration, and co-essentiality network analyses. PSMB5 and PSMB6 were prioritized as robust cross-platform and cross-lineage dependency biomarkers, exhibiting reproducible and selective vulnerability patterns across diverse malignancies. Their dependency strength was quantitatively associated with immune-related signaling pathways, including MHC and interferon responses, and inversely correlated with key immune regulatory genes such as NLRC5 and IRF1. Co-essentiality network analysis revealed modular functional organization of proteasome-associated genes, supporting context-dependent roles rather than uniform essentiality. Importantly, the association between proteasome subunits and tumor immune context was externally validated through meta-analysis across 24 independent hepatocellular carcinoma cohorts, demonstrating reproducible correlations with CD4-positive T cell, CD8 T cell, and macrophage infiltration signatures. Functional validation further confirmed that siRNA-mediated knockdown of PSMB5 and PSMB6 significantly impaired proliferation across multiple hepatocellular carcinoma cell lines. Collectively, this study prioritizes PSMB5 and PSMB6 as consistently associated functional biomarkers that integrate genetic dependency and immune context, providing a data-driven framework for stratifying proteasome-targeted therapeutic strategies across cancers. Full article

Background/Objectives. Breast cancer is the most frequently diagnosed cancer worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR), and the lack of HER2 overexpression, limiting use of targeted therapies. Current TNBC treatment relies heavily on chemotherapy, most commonly taxanes including paclitaxel that stabilize microtubules, disrupt chromosome separation and induce apoptosis. TNBCs frequently develop chemoresistance after multiple treatment cycles, highlighting a critical unmet need for novel therapeutic strategies. This study addresses this challenge by targeting salt-inducible kinase 2 (SIK2), which is overexpressed in 85% of TNBCs compared to normal breast tissue. Methodes. In collaboration with Arrien Pharmaceuticals and Greenfire Biologics, we developed ARN-3261/GRN-300, a novel orally bioavailable SIK2 inhibitor and evaluated its ability to sensitize TNBC cells to paclitaxel in vitro and in vivo. Results. GRN-300 demonstrated strong synergy with paclitaxel in all eight TNBC cell lines tested, as indicated by favorable combination indices. In xenograft models, the combination therapy significantly enhanced tumor growth inhibition and prolonged survival compared to either agent alone. Mechanistic studies showed that GRN-300 disrupts the anaphase-promoting complex/cyclosome (APC/C) pathway by downregulating key mitotic regulators, including CDC27, CDK1, and PLK1, thereby potentiating G2/M cell cycle arrest and apoptosis. Conclusions. Together, these findings establish GRN-300 as a promising therapeutic agent that enhances paclitaxel efficacy through complementary disruption of mitotic regulatory pathways, providing strong preclinical rationale for clinical development in TNBC. Full article

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BrCa), owing to its lack of targetable receptors and resistance to chemical and molecularly targeted therapeutic approaches. While chemotherapy and surgical resection remain the standard of care, these interventions have significant side effects and varying patient outcomes. Thermally ablative focused ultrasound (T-FUS)—a non-invasive and non-ionizing therapy that utilizes targeted acoustic energy to debulk tumors—has displayed immunomodulatory effects in BrCa. However, T-FUS as a monotherapy has had limited clinical efficacy in TNBC due to the presence of anti-inflammatory immunosuppressive myeloid cells (isMCs). We hypothesized that the elimination of isMCs or initiating tumoricidal activity from them would lead to augmented activity of T-FUS. Thus, we interrogated the ability of myeloablative chemotherapies and antibodies; myeloid recruiting chemokine receptor blockade; and TLR agonists to remodel the tumor myeloid populations. Consistent with our previous studies, we found that while myeloablative chemotherapies decreased circulating isMCs, they had little impact on intratumoral isMCs. In contrast, antibodies targeting Ly6C and Ly6G ablated intratumoral isMCs and systemic isMCs, yet their effect was transient and was accompanied by a surprising depletion of T cells. While targeting CCR2, the dominant chemokine receptor for intratumoral isMC diminished a large subset of immunosuppressive cells within the TME; it also depleted T cells and dendritic cells. Contrary to previous studies, TLR stimulation failed to repolarize myeloid cells into a pro-inflammatory, tumoricidal phenotype but did lead to their depletion from the tumor microenvironment (TME) and mobilization of conventional dendritic cells to the draining lymph nodes. We therefore hypothesized that combining isMC depletion and TLR-driven immune activation would enhance FUS efficacy; however, this combinatorial regimen did not enhance overall survival or control tumor volume after T-FUS treatment. Thus, the BrCa TME is highly resistant to approaches intended to remodel the myeloid cell component which fail to synergize with T-FUS-mediated tumor ablation. Full article

Cancer remains a major global health challenge, with persistent limitations in early diagnosis, metastatic disease control, and the achievement of durable therapeutic responses with acceptable toxicity. These challenges highlight the need for more precise biomarkers and more effective therapeutic strategies. Increasing evidence implicates dysregulated lipid metabolism as a central contributor to tumor development and progression. In recent years, proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), and cholesteryl ester transfer protein (CETP) have gained particular attention due to their roles in cholesterol homeostasis, oncogenic signaling, and immune modulation within the tumor microenvironment (TME). This narrative review evaluates the potential of these lipid-regulatory mediators as diagnostic biomarkers and therapeutic targets in oncology. The majority of available evidence derives from preclinical and epidemiological studies, with PCSK9 representing the most extensively investigated target. Findings are sometimes contradictory and strongly influenced by tumor type, disease stage, and biological context, which currently precludes the clinical applicability of these molecules as reliable biomarkers. Similar limitations apply to their translational potential as actionable therapeutic targets. Nevertheless, emerging preclinical evidence suggests that modulation of these glycoproteins may enhance the efficacy of chemotherapy, targeted therapies, and immunotherapy, including nanomedicine-based approaches. Of note, clinical research investigating the role of PCSK9 inhibition in oncology is currently ongoing, whereas comparable studies focusing on ANGPTL3 and CETP remain scarce. Overall, further mechanistic, translational, and prospective clinical investigations are warranted to elucidate the involvement of these lipid-regulatory proteins in cancer biology and to define their potential integration into future oncologic diagnostic and therapeutic strategies. Full article

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction is increasingly recognized as a key contributor to a broad spectrum of human diseases beyond classical cystic fibrosis (CF). CFTR is a cAMP-regulated chloride and bicarbonate ion channel expressed in both epithelial and non-epithelial tissues, where it regulates ion homeostasis, mucosal hydration, and cellular signaling. Both inherited CFTR mutations and acquired dysfunction resulting from environmental or inflammatory factors can disrupt these physiological processes and drive disease progression. Current evidence linking CFTR dysregulation to respiratory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, and HIV-associated airway disease, as well as cardiovascular, renal, neurological diseases, and cancer, is comprehensively discussed. Mechanistically, impaired CFTR function promotes oxidative stress, chronic inflammation, epithelial barrier dysfunction, altered mucociliary clearance, and dysregulation of signaling pathways, including NF-κB, TGF-β, PI3K/Akt, MAPK, and Wnt/β-catenin. In the context of HIV infection and cigarette smoke exposure, CFTR suppression is mediated in part by TGF-β signaling and miRNA-dependent mechanisms, resulting in compromised airway defense and increased susceptibility to pulmonary complications. Recent studies further demonstrate that CFTR dysregulation alters the expression of genes involved in fibrosis, inflammation, angiogenesis, and epithelial–mesenchymal transition (EMT). Notably, CFTR may act as either a tumor suppressor or a context-dependent oncogene, depending on tissue type and signaling milieu, highlighting its complex role in cancer biology. Advances in CFTR-targeted therapies, including potentiators, correctors, gene therapy, and combination approaches, have markedly improved outcomes in CF and may offer therapeutic potential for diseases associated with acquired CFTR dysfunction. We summarize the systemic consequences of CFTR dysregulation and the need for further mechanistic and translational research to clarify its role across diverse human diseases. Full article

Neuroblastomas (NBs) are aggressive, therapy-resistant embryonal tumors of neural crest origin, which despite low mutational burdens exhibit high intra-tumoral heterogeneity characterized by adrenergic, noradrenergic, mesenchymal and cancer stem cell (CSC)-like subpopulations. These phenotypes exhibit interconverting plasticity that reflect both stage of transformation during sympathoadrenal development and conditions within the tumor microenvironment. Chemotherapeutic agents promote adrenergic-to-mesenchymal conversion in NBs, which underpins drug resistance, post-therapeutic relapse, metastatic progression, and the plateauing of responses to advances in multimodal therapy. Improved understanding of the molecular mechanisms that regulate NB phenotypic plasticity is essential for identifying novel prognostic markers and potential therapeutic targets. In this article, following introductions into NB, molecular regulation of NB phenotypic plasticity, and the NF-Y transcription factor and its role in development and differentiation, we focus on alternative NF-YAl, NF-YAs and NF-YAx splicing of the NF-Y subunit, NF-YA, and the potential influence that different NF-YA isoforms have on NF-Y function and the NF-Y-transcription factor networks that impact NB cell phenotypes. Particular attention is paid to the novel extra short-form NF-YAx isoform, originally detected as the exclusive NF-YA isoform in a non-MYCN amplified advanced stage 3 NB. This isoform is also induced by doxorubicin in non-Myc amplified SH-SY5Y NB cells and is involved in doxorubicin cytotoxicity. Despite high cytotoxicity, however, NF-YAx selects a resistant subpopulation with mesenchymal/neural crest stem cell-like identity, unveiling a doxorubicin-induced NF-YAx-dependent resistance mechanism, with potential to influence post-therapeutic relapse and disease progression. Therefore, evaluating alternative NF-YA splicing, and especially NF-YAx expression, in advanced stage and post-therapeutic relapsed NBs, may be of both prognostic and therapeutic significance. Full article

The therapeutic landscape of advanced and recurrent endometrial cancer (EC) has evolved substantially in recent years due to the integration of molecular classification and novel systemic therapies. This review summarizes current treatment strategies in advanced EC, focusing on immunotherapy, targeted therapies, and molecularly guided approaches. Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment, particularly in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) tumors, where durable clinical benefit has been observed. Recent phase III trials demonstrated that the addition of ICIs to platinum-based chemotherapy significantly improves progression-free survival in the first-line setting, especially in dMMR disease, with more modest but clinically meaningful benefit in mismatch repair-proficient (pMMR) tumors. In the post-platinum setting, combinations such as pembrolizumab plus lenvatinib have expanded treatment options for pMMR patients, despite increased toxicity. Advances in molecular profiling, including the ProMisE classification, are increasingly guiding treatment personalization. Emerging therapies, including PARP inhibitors and antibody–drug conjugates targeting HER2 and Trop-2, are showing promising activity. Despite these advances, challenges remain regarding resistance mechanisms, optimal treatment sequencing, and predictive biomarkers beyond MMR status. Full article

Background/Objectives: Adoptive transfer of allogeneic natural killer (NK) cells represents a promising off-the-shelf immunotherapy for cancer, offering advantages in safety and availability over autologous T cell therapies. However, generating therapeutically sufficient NK cell numbers remains challenging due to their low frequency in blood sources. Engineered feeder cell co-cultures have enabled substantial expansions of NK cells to clinically relevant doses. Methods: We evaluated the plasma cell leukemia-derived ARH-77 cell line as a feeder for ex vivo NK cell expansion from healthy donor peripheral blood mononuclear cells (PBMCs). Unmodified ARH-77 was compared to K562, followed by engineering both lines to co-express B7-H6 (NKp30 ligand), CD137L (4-1BBL), IL-15, and IL-15Rα via sequential lentiviral transduction. PBMCs were co-cultured with irradiated feeders in cytokine-supplemented (IL-2, IL-21, and later IL-15) RPMI-1640 or DMEM/F-12 medium for up to 28 days. Expansion (fold change in CD3⁻CD56⁺ cells), purity, surface receptor expression, and cytotoxicity (against K562 targets) were quantified. Results: Unmodified ARH-77 supported significantly greater NK cell expansion than K562 (model-estimated 681-fold vs. 155-fold at week 4 in RPMI; p = 0.0018), with higher purity but comparable cytotoxicity and receptor profiles. Engineered ARH-77 cells achieved robust expansion in RPMI, comparable to that of engineered K562 cells. In optimized DMEM/F-12 medium, engineered ARH-77 drove superior expansion (up to model-estimated 101,241-fold; 95% CI 46,771–219,146 at week 4), significantly outperforming engineered K562 (4.4-fold greater; 95% CI 1.01 to 18.54; p = 0.0479) while maintaining high purity and equivalent cytotoxicity. Substantial inter-donor variability influenced expansion magnitude, though relative feeder performance remained consistent across donors. Conclusions: Genetically modified ARH-77 feeder cells provide a potent platform for large-scale ex vivo expansion of functional NK cells. Full article

Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a “versatile player” in oncology. It exerts a dual, context-dependent role in cancer, acting as both a potent tumor suppressor and a facilitator of tumor progression and therapeutic resistance. This review systematically delineates the core molecular regulatory networks of ferroptosis, highlighting the intricate balance between its execution mechanisms—driven by polyunsaturated fatty acid (PUFA) oxidation, iron catalysis, and mitochondrial dysfunction—and the robust endogenous defense systems, including the GSH-GPX4, FSP1/DHODH-CoQ10, and GCH1-BH4 axes. We deeply explore the dichotomous nature of ferroptosis in tumorigenesis: while classical tumor suppressors like p53 and CDKN2A harness ferroptosis to halt tumor growth, cancer cells can hijack lipid metabolic reprogramming and specific enzymes (e.g., iPLA2β) to evade cell death and promote distant metastasis. Furthermore, we dissect the multidimensional crosstalk between ferroptosis and the tumor microenvironment (TME), emphasizing its bidirectional immunoregulatory effects. Although CD8+ T cell-derived IFN-γ can sensitize tumor cells to ferroptosis and amplify anti-tumor immunity, aberrant ferroptotic activation can paradoxically foster an immunosuppressive niche. Finally, we summarize the latest translational strategies using small-molecule inducers and synergistic combination therapies, emphasizing that biomarker-guided patient stratification remains the ultimate paradigm for overcoming resistance and realizing precision ferroptosis-targeted cancer therapy. Full article

Mitochondria play essential roles in cellular metabolism and signaling, regulating biosynthetic pathways, calcium homeostasis, redox balance, and cell fate beyond ATP production. Their continual remodeling through fusion, fission, and mitophagy maintains mitochondrial quality control and adapts organelle function to cellular demands. Here, we review how mitochondrial dynamics, fusion, fission, and mitophagy modulate metabolic reprogramming and signaling to drive cancer progression and therapy resistance. Emerging evidence indicates that in cancer, mitochondrial fusion enhances respiratory efficiency and oxidative phosphorylation, whereas fission promotes glycolytic adaptation, rapid biomass accumulation, and stress tolerance. Mitophagy further refines metabolic fitness by eliminating damaged mitochondria and sustaining redox homeostasis. Together, these processes underscore that dysregulation of mitochondrial dynamics is a hallmark of cancer and a key driver of metabolic reprogramming and therapeutic resistance. In this review, we summarize how mitochondrial fusion, fission, and mitophagy govern metabolic circuitry in cancer development and therapy resistance. We highlight their functional impact on tumor progression and discuss emerging therapeutic strategies targeting mitochondrial dynamics and associated machinery. Understanding this dynamic metabolic crosstalk may reveal new vulnerabilities and guide the development of mitochondria-targeted cancer therapies. Full article

Background: Systematic neoadjuvant therapy (NAT) is recommended for triple-negative (TNBC) and HER2+ breast cancers when tumor size at diagnosis is ≥2 cm. This study aimed to determine the proportion of patients in Nova Scotia with non-metastatic, incident, ≥2 cm TNBC and HER2+ breast cancer who received guideline-concordant NAT, stratified by administrative zone. Methods: This retrospective analysis utilized data from the Nova Scotia Breast Screening Program. Adult patients (18–80 years) with an incident, non-metastatic, ≥T2 breast cancer diagnosis between 2021 and 2023 were considered theoretically eligible for NAT, defined by a wait time of ≥4 months between core biopsy and surgery. Guideline-concordant care was confirmed through chart review and compared across health system administrative zones and over time. Results: Of the 291 women theoretically eligible for NAT, 67.0% received it. Significant differences in NAT receipt were observed across administrative zones (Central 73.1%, Eastern 72.9%, Northern 57.4%, Western 54.2%, p = 0.030). Conclusions: This study identifies meaningful regional disparities in NAT receipt for TNBC and HER2+ breast cancer in Nova Scotia. Targeted strategies to improve guideline concordance are warranted and may lead to better patient outcomes. Full article

Multidrug resistance remains a major obstacle in gastric cancer therapy and is frequently associated with aggressive phenotypes. Although ABCG2 is a well-known drug efflux transporter, its functional contribution to paclitaxel (PTX) resistance and its relationship with ERK signaling in gastric cancer remain incompletely understood. In this study, PTX-resistant gastric cancer cell models were established through prolonged drug exposure. Resistant cells exhibited cross-resistance to cisplatin and 5-fluorouracil together with enhanced drug efflux activity, invasion capacity, spheroid formation, stemness-associated marker expression, and G0/G1 enrichment. ABCG2 expression was markedly increased in resistant cells. Stable knockdown of ABCG2 restored PTX sensitivity and significantly reduced drug efflux, invasion, spheroid formation, and stemness-associated phenotypes, while increasing apoptosis and altering cell cycle distribution. ABCG2 depletion was associated with reduced ERK phosphorylation and decreased expression of ERK downstream target genes. Pharmacological inhibition of ERK signaling similarly suppressed resistance-associated phenotypes and reduced ABCG2 expression. Whereas reactivation of ERK signaling by constitutively active MEK1 partially rescued the effects of ABCG2 depletion, restoring aggressive and multidrug-resistant phenotypes. Our findings indicate that ERK signaling functionally contributes to ABCG2-associated multidrug resistance and aggressive phenotypes in PTX-resistant gastric cancer cells. Full article

The tumor microenvironment of breast cancer presents high complexity and resistance to conventional therapies. Ferroptosis, a programed cell death that is dependent on iron and characterized by lipid peroxidation, arises as a promising therapeutic goal. This scoping review mapped evidence on the exogenous use of iron and selenium, in conventional or nano-particulated forms, in the modulation of ferroptosis as therapeutic strategy for breast cancer treatment, identifying knowledge gaps and opportunities for future research. We performed a scoping review and the methodology followed the guidelines of the Joanna Briggs Institute (JBI) and PRISMA-ScR. We made a systematic search in five data bases (Embase, Lilacs, PubMed (MEDLINE), Scopus, and Web of Science) between the years 2012 and 2025. Among 2.723 identified publications, we selected 48 studies. The results revealed predominance of nanoplatforms of iron (97.9%), focused on the Fenton reaction. The modulation of selenium for inactivation of GPX4 was shown to be effective, though still little-explored (n = 1). We evidenced that the induction of ferroptosis potentializes tumor immunogenicity and the effectiveness of combined therapies. We conclude that the field is under development; thus, the diversification of metabolic targets and trials of chronic toxicity are fundamental steps for future clinical research. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the most complex and aggressive disease with the worst rates of unresectable or metastatic disease at diagnosis, resistance to systemic therapy, and case fatality rate (CFR) among leading cancers. In non-metastatic disease, neoadjuvant treatment with modern chemotherapeutic regimens followed by surgical resection and/or adjuvant mFOLFIRINOX has significantly improved oncological outcomes. However, recurrence rates remain alarmingly high, while immune checkpoint inhibitors (ICIs) or molecularly targeted therapy have not yet demonstrated clinical benefits. Comprehensive genomic profiling through NGS-based approved assays such as TruSight Oncology 500 (TSO500) could guide targeted therapy. Rapidly evolving mRNA cancer vaccines and circulating tumor DNA (ctDNA)-based prediction of minimal residual disease (MRD) and recurrence risk hold great promise towards the realization of rational combination therapy to improve recurrence-free survival (RFS) and overall survival (OS). More recently, single-cell multiomics (SC MO), spatial proteomics and transcriptomics (SPT), artificial intelligence (AI), and systems biology have revolutionized cancer research, enabling holistic tumor microenvironment (TME) analysis. In this comprehensive review, we describe the latest advances and unmet needs in the standard of care of PDAC. Moreover, we discuss the expectations of ongoing randomized clinical trials of adjuvant mRNA vaccine-based therapy and ctDNA MRD testing as prognostic biomarkers, towards personalized treatment to improve RFS and OS in a medium-term perspective. With a longer perspective, we explore how harnessing SC MO, SPT, AI, and systems biology can reveal the 3D spatial organization of interacting cancer, immune, and stromal cells. Multi-dimensional TME-, TSO500- and ctDNA-based framework of dynamic biomarkers are of paramount importance to achieve an optimal patient-specific perioperative multimodal treatment combining precision immunotherapy, targeted drugs, and modern chemotherapy, translated into future practice-changing clinical trials, that could eliminate MRD towards recurrence prevention. Full article