Radioresistance compromises pancreatic cancer radiotherapy outcomes, making the identification of radiosensitizing strategies a critical priority. AZD5153, a novel specific Bromodomain-containing protein 4 (BRD4) inhibitor, has demonstrated efficacy in relapsed/refractory solid tumors and lymphomas. Our research focuses on investigating the effect of AZD5153 on the radiotherapy sensitivity of human pancreatic cancer cells, and its underlying mechanisms.

Cetuximab is an approved therapy for metastatic colorectal cancer (CRC) with wild-type RAS and BRAF; however, additional resistance mechanisms beyond genetic mutations remain poorly understood. Butyrate, a key metabolite produced by the gut microbiome and present in the circulatory system, has been reported to supply cellular energy and modulate the epidermal growth factor receptor (EGFR) downstream signaling pathway. However, whether butyrate affects the resistance to cetuximab is still unknown.

Vepdegestrant (ARV-471) is an orally bioavailable, proteolysis-targeting chimera (PROTAC)-based estrogen receptor (ER) degrader and is among the most clinically advanced ER-targeting PROTAC degraders, identified through a rational medicinal chemistry optimization campaign. It is being developed as an oral small-molecule endocrine therapy for advanced or metastatic ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, with particular relevance for tumors harboring ESR1 mutations. On June 6, 2025, Arvinas and Pfizer submitted a New Drug Application (NDA) for vepdegestrant to the U.S. Food and Drug Administration (FDA), representing an important step in the clinical translation of PROTAC technology. This review summarizes the design, synthesis, degradation mechanism, preclinical pharmacology, and clinical development of vepdegestrant and discusses the broader implications and future prospects of oral PROTAC-based ER degraders in breast cancer therapy.

Advances in cancer treatment have led to improved survival rates, but challenges related to health-related quality of life (HRQoL) persist, often exacerbated by sleep disturbances. We present a pre-registered, secondary analysis of HRQoL from a trial of sleep interventions among women with early or advanced breast cancer receiving chemotherapy.

The aim of this work was to develop dendrimer-based nanocarriers of Vismodegib (VDG) for the topical treatment of Kaposi's sarcoma (KS). Previous molecular docking studies have shown that VDG is capable of inhibiting cyclooxygenase-2 (COX-2), an enzyme transcriptionally induced by the viral oncoprotein vGPCR and critically involved in the angioproliferative phenotype of KS. In this study, VDG was complexed with generation 4 poly(amidoamine) (PAMAM) dendrimers bearing hydroxyl terminal groups (G4-OH), and surface-functionalized with folic acid (G4-FA). The resulting G4-OH@VDG and G4-FA@VDG complexes significantly enhanced the apparent aqueous solubility of VDG, achieving experimental stoichiometries of approximately 4 and 8 mol of VDG per mole of dendrimer, respectively. G4-OH@VDG displayed a hydrodynamic diameter of 225.1 ± 122.0 nm (PdI = 0.44 ± 0.02), while G4-FA@VDG exhibited a size of 210.5 ± 54.7 nm (PdI = 0.66 ± 0.08). Dendrimer-drug associations were confirmed by FT-IR spectroscopy, and in vitro release studies revealed distinct, pH-dependent release mechanisms. Cytotoxicity was evaluated using ex vivo (red blood cells) and in vitro (HaCaT keratinocytes) models, both relevant to topical KS treatment, and no cytotoxic effects were observed. Skin penetration studies using the Saarbrücken ex vivo model demonstrated that both systems were able to deliver VDG into the skin, with G4-OH@VDG achieving higher drug accumulation, particularly within the stratum corneum. Antitumoral activity was assessed in an in vitro KS model, where cytotoxic effects were observed at 48 h post-incubation. Notably, G4-OH@VDG exhibited the most favorable therapeutic profile, including significant reduction of cell viability and inhibition of cell migration at sublethal concentrations. Overall, these results demonstrate that the combination of drug repurposing and dendrimer-based nanotechnology for topical delivery enhances the therapeutic performance of VDG in in vitro models of Kaposi's sarcoma.

This study aimed to comprehensively investigate the anti-ovarian cancer (OC) efficacy of Yiyi Fuzi Baijiang Powder (YFBP), identify its key chemical constituents, and elucidate the underlying mechanisms of action.

Ovarian cancer is a leading gynecological malignancy with a poor patient survival rate. The current therapeutic regimen primarily relies on chemotherapy. However, most patients experience relapse and develop chemoresistance. Therefore, there is an urgent need to develop new anti-ovarian cancer compounds and scalable production processes. Dimethyl bisphenolate (DMB), a novel compound that we synthesized, is a phenolic acid derivative based on the neolignan backbone. The compound was produced by degrading and esterifying salvianolic acid B, the primary active ingredient in Salvia miltiorrhiza Bge. This study evaluated the anti-ovarian cancer activity of DMB through in vitro and in vivo experiments. DMB effectively inhibited the proliferation and migration of ovarian cancer cells in vitro. Mechanistic studies demonstrated that DMB suppresses ovarian cancer cell growth by regulating the PI3K/AKT/mTOR signaling pathway, impairing energy metabolism, and inducing cell cycle arrest and apoptosis. In vivo experiments further confirmed DMB significantly inhibited tumor growth in a human ovarian cancer nude mouse xenograft model. Overall, the significant anti-ovarian cancer effect demonstrated, the underlying mechanisms elucidated, and the scalable preparation technology established indicate that DMB is a promising therapeutic candidate for treating ovarian cancer.

The persistent challenges posed by ovarian cancer, marked by its high mortality rates and resistance to conventional therapies, drive a continuous search for innovative and effective treatment strategies. In the current study, laurus nobilis extract was loaded into chitosan nanoparticles to investigate its potential anti-cancer effects against SKOV3 ovarian cancer cells.

The glycoengineered humanized monoclonal type II anti-CD20 antibody obinutuzumab is widely used in the treatment of patients with chronic lymphocytic leukemia (CLL), most commonly in combination with other therapeutic agents. The aim of this single-centre retrospective study was to evaluate the treatment patterns and clinical responses in patients with CLL treated with obinutuzumab-based combination regimens at the University Clinic of Hematology, Skopje. We analyzed 90 patients with CLL treated with obinutuzumab-based regimens between 2019 and 2024. Obinutuzumab was administered in combination with chlorambucil (56.6%), fludarabine-cyclophosphamide (26.6%), bendamustine (11.1%), CVP (4.4%), or venetoclax (5.5%). The treatment was given as first-line therapy in 57.7% of patients and in the relapsed/refractory setting in 42.3%. The median age at initiation of obinutuzumab-based therapy was 66.9 years. The overall response rate to obinutuzumab-based treatment was 45.5%. The median follow-up after treatment was 15.6 months. In this real-world single-centre experience, obinutuzumab-based combination regimens showed measurable clinical activity in routine practice across different treatment lines. Longer follow-up and larger patient cohorts are required to better characterize the durability of the responses and outcomes in the specific treatment subgroups.

Head and neck squamous cell carcinoma (HNSCC) arises from the squamous epithelium of the head and neck region, comprising heterogeneous lesions with distinct risk factors and diverse genetic and epigenetic alteration patterns. HNSCC is often difficult to control when lymph node metastasis has occurred, and treatment outcomes remain unsatisfactory. Elucidating the genetic and epigenetic profiles of cancer-associated genes is essential for improving clinical outcomes, yet to date the key molecules driving HNSCC progression remain unclear.

Junctophilin 3 (JPH3) acts as a tumor suppressor in several cancers; however, the role of JPH3 in anaplastic thyroid cancer (ATC) is still unknown.

Over half of esophageal cancer (EC) cases occur in China, where paclitaxel and platinum agents have become the preferred chemotherapeutic regimen for EC patients. However, there is a clinical need for a non-platinum-based therapeutic option.

Salidroside (SAL) is a natural glycoside compound with various biological activities. Recent studies have shown that SAL exhibits certain therapeutic effects on triple-negative breast cancer (TNBC). To enhance the anti-TNBC activity, 15 SAL-furoxan hybrids were designed and synthesized. The anti-proliferative activities of all target compounds against four tumor cell lines (MDA-MB-231, MCF-7, BGC-823, and A549) and a normal human cell line (MCF-10A) were evaluated using the MTT assay. A12 demonstrated the most potent inhibitory activity on MDA-MB-231 cells (IC₅₀ = 14 nM), and lower toxicity compared to DOX (SI = IC50(MCF-10A)/IC50(MDA-MB-231): 129.57 vs 1.01). Further research indicated that the anti-tumor mechanism of A12 involves the high amount of NO released in MDA-MB-231 cells and thereby induction of cells apoptosis.

Patient-reported outcomes (PROs) are increasingly recognised for their role in assessing tolerability in dose-finding oncology trials (DFOTs). However, analysis and reporting of PRO data within DFOTs are often unclear and inconsistent. OPTIMISE-AR (Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Analysis Recommendations) establishes a practical toolkit supporting the statistical analysis, visualisation, and reporting of PRO data within DFOT publications. International, multidisciplinary, cross-sector statistical analysis and data visualisation working groups identified analytical and visualisation approaches for PROs data, addressing key DFOT PRO research objectives. Informed by existing literature, case studies and recommendations are provided in this Policy Review for analysing binary, ordinal, and continuous PRO data to assess tolerability across doses and timepoints, and to integrate PROs into interim and final dose-decision processes. The OPTIMISE-AR toolkit is structured around four methodological domains aligned with key DFOT PRO research objectives, providing statistical analysis and data visualisation recommendations for (1) PRO endpoints across timepoints, (2) PRO endpoints between timepoints, (3) time-to-event PRO endpoints, and (4) PRO endpoints for formal dose-decision making in model-based dose-finding designs. As PROs have an increasing role in tolerability assessment, this Policy Review promotes analysis and data visualisation of PRO data, facilitating robust, patient-centred tolerability conclusions and supporting the broader development of tolerable and effective treatments.

Uterine leiomyosarcoma (Ut-LMS) is a rare and aggressive gynecologic malignancy with limited effective therapeutic options. In this study, we investigated the cytotoxic effects and underlying mechanisms of bortezomib in Ut-LMS cell lines SK-LMS-1 and SK-UT-1B. Bortezomib treatment significantly reduced cell viability and increased lactate dehydrogenase release, indicating pronounced cytotoxicity. Apoptotic cell death was induced, as evidenced by increased Annexin V-positive cell populations. Bortezomib also suppressed proliferative activity, reflected by reduced Ki67 expression, and induced G2/M cell cycle arrest in SK-LMS-1 cells, whereas SK-UT-1B cells exhibited minimal alterations in cell cycle distribution. In addition, bortezomib increased reactive oxygen species production in SK-UT-1B cells and induced mitochondrial membrane depolarization in both cell lines, while antioxidant treatment attenuated bortezomib-induced apoptosis in SK-UT-1B cells, indicating partial involvement of oxidative stress. Western blot analysis further revealed enhanced cleavage of poly(ADP-ribose) polymerase and caspase-3, along with modulation of cell cycle regulatory proteins, including upregulation of p21 and differential regulation of p53 between the two cell lines. Finally, autophagy-related analyses demonstrated increased LC3B-II levels accompanied by p62 accumulation, suggesting altered autophagic processing rather than simple activation of autophagy. Collectively, these findings demonstrate that bortezomib exerts cytotoxic effects in Ut-LMS cells through coordinated regulation of proteasome inhibition-associated apoptosis, cell cycle control, mitochondrial dysfunction, and autophagy-related signaling, with cell line-specific differences in stress response pathways.

Given the high incidence of hepatocellular carcinoma (HCC) and its limited therapeutic options, and building on our previous work on anti-HCC sesquiterpenoid dimers, a series of natural product-like guaianolide-eudesmanolide dimers were designed and synthesized as potential anti-HCC agents in this study. Among them, compound 1 showed significantly antihepatoma effects on HepG2, Huh-7, and SK-Hep-1 cells with IC50 values of 5.6, 4.8, and 4.6 μM, respectively; induced cell cycle arrest and apoptosis; and inhibited the migration of HCC cells. Bioinformatic analysis and experimental validation indicated that compound 1 directly targeted NEURL1B, which was further established as a critical regulator of HCC proliferation and migration. Mechanistically, compound 1 bound to Arg422 within the NHR2 domain of NEURL1B, triggering its autoubiquitination and degradation, which stabilized DLL1 by suppressing its ubiquitination and ultimately attenuated the Notch signaling pathway. In vivo experiments showed that compound 1 (60 mg/kg) inhibited tumor weight up to 69% in SK-Hep-1 xenograft nude mice, which was comparable to that of sorafenib (67%) at the same dose. This study revealed that the previously unrecognized oncogenic role of NEURL1B acted as upstream of DLL1 in HCC, and suggested that compound 1 might be an antihepatoma candidate that inhibited Notch signaling by disrupting the NEURL1B-DLL1 interaction.

Enzalutamide is a potent androgen receptor (AR) inhibitor widely used for the treatment of castration-resistant prostate cancer (CRPC). However, the development of drug resistance severely limits its therapeutic efficacy, and the underlying mechanisms remain poorly understood. We have demonstrated that decorin (DCN), a suppressor of prostate cancer (PCa) progression, is significantly down-regulated in enzalutamide-resistant PCa cells. Therefore, we hypothesized that diminished expression of DCN contributes to enzalutamide resistance in PCa. In this study, we found that DCN was decreased in enzalutamide-resistant LNCaP cells (LNCaP-ER), which exhibited resistance to ferroptosis. Consistently, DCN was significantly reduced in high-grade PCa and CRPC tissues, as well as in those with poor clinical survival outcomes through integrative analysis. Moreover, DCN overexpression re-sensitized LNCaP-ER cells to enzalutamide by activating ferroptosis. What's more, DCN overexpression significantly inhibited tumor growth and metastasis of LNCaP-ER cells in vivo under enzalutamide-treated conditions, in a ferroptosis-dependent manner. Mechanistically, DCN activated calcium-dependent Protein Kinase C Beta II (PKCβII), thereby enhancing phosphorylation of long-chain acyl-CoA synthetase 4 (ACSL4) to regulate lipid remodeling and promote ferroptosis. In addition, enzalutamide-mediated AR nuclear translocation negatively regulates DCN transcription. In conclusion, promoting DCN-mediated ferroptosis might be a potential strategy for enhancing the sensitivity of enzalutamide in PCa cells. This study delineates a novel mechanism by which DCN downregulation suppresses ferroptosis and drives enzalutamide resistance in CRPC.

Chemodynamic therapy (CDT) holds significant promise for tumor-selective treatment; however, its therapeutic performance is frequently hampered due to the insufficient endogenous hydrogen peroxide (H2O2) and strict Fenton reaction conditions. Herein, an innovative cascade-amplified nanoreactor is synthesized through a solvothermal approach, with F127 serving as a structure-directing soft template to construct hollow manganese ferrite nanoparticles (HMF), further coated with polydopamine (HMFP) and loaded with glucose oxidase (GOx) (HMFPG). Within the tumor microenvironment, glucose is oxidized by the released GOx to form gluconic acid and H2O2, inducing tumor starvation while generating additional H2O2 for the Fenton reaction. Simultaneously, Mn2+ catalyzes H2O2 decomposition to produce O2, which further promotes GOx-mediated glucose oxidation and sustains the cascade catalytic reaction. The self-supplied H2O2 and O2 effectively enhance the dual catalytic centers (Fe3+/Mn2+)-mediated Fenton and Fenton-like reactions, producing abundant ·OH radicals. Moreover, the photothermal effect of HMFP accelerates the Fenton reaction rate, establishing a positive feedback process for CDT. Both in vitro cellular and in vivo animal studies demonstrate that the integrated CDT/photothermal therapy (PTT)/starvation therapy (ST) achieves remarkable antitumor efficacy. Overall, this self-sufficient nanoplatform (HMFPG) significantly boosts CDT performance by integrating dual catalytic centers, autonomous H2O2/O2 generation and photothermal amplification. This breakthrough provides a novel nanoplatform and promising conceptual advancement for enhanced multimodal tumor therapy.

Cellular stresses regulate transcriptional readthrough, whereby RNA polymerase II elongates past a gene's polyadenylation cleavage site without RNA cleavage. Readthrough has been reported in several cancer types. Here, we use long-read sequencing of nascent RNA to quantify transcriptional readthrough in chronic myeloid leukemia (CML) cells and characterize early responses to the targeted therapeutic, imatinib. We show that the amount, length, and gene specificity of readthrough increase within 1 hour, before gene expression and alternative splicing alterations emerge. Notably, imatinib-dependent messenger RNA (mRNA) isoform changes involved "readthrough chimeras," in which exons from an upstream gene are alternatively spliced to exons in a downstream gene. Altered mRNA isoforms and chimera levels were detected in imatinib-resistant K562 cells as well as cells of patients with CML. Thus, imatinib can provoke a cascade of early changes to transcription and splicing fidelity that may lead to longer-term adjustments in gene expression, cancer cell differentiation, and the development of therapy resistance.

Talquetamab (TAL), a first-in-class bispecific antibody targeting GPRC5D and CD3, has demonstrated high efficacy in heavily pretreated relapsed and refractory multiple myeloma (RRMM), achieving response rates of approximately 70%. However, TAL is frequently associated with on-target, off-tumor oral toxicities.