ABL-rearranged (ABLr) acute lymphoblastic leukemia (ALL) is associated with treatment failure and relapse and novel treatments are required. We investigated asciminib efficacy against NUP214::ABL1 ALL, the second most common ABL1 rearrangement associated with aggressive disease. Asciminib activity was established in three patient derived xenograft models of NUP214::ABL1 ALL with different ABL1 breakpoints (e31a2, e32a3, e34a3). In all models, treatment with asciminib reduced NUP214::ABL1 leukemic burden and increased survival outcomes compared with control mice. These results contrast with recent in vitro studies in the setting of BCR::ABL1 leukemia, where ABL1 exon 3 breakpoints (e13a3, e14a3) result in asciminib resistance due to incomplete SH3 domain. Conversely, in silico modeling of NUP214::ABL1 e32a3 predicted NUP214 exon 32 mimics the missing ABL1 exon 2, forming a chimeric SH3 domain that rescues asciminib sensitivity. This prediction was supported by viability assays of Ba/F3 cells expressing NUP214::ABL1 with exon 32 present and absent. Additional viability assays and structural modeling of NUP214::ABL1 Ba/F3 cells expressing various ABL1 deletions defined a region of the SH3 domain critical for asciminib efficacy and necessary for allosteric inhibition. Our findings establish asciminib as a potential treatment for NUP214::ABL1 ALL and reveal a critical role for the fusion partner gene. Asciminib efficacy in ABLr leukemia cannot be predicted by evaluating ABL1 exon 2 inclusion/exclusion in isolation. This is of clinical importance as first-line use of STAMP inhibitors such as asciminib becomes more common.

Ovarian cancer, with metastasis and chemoresistance being the major obstacles to successful treatment, is a leading cause of death among gynecological malignancies. Identifying new molecular targets and understanding the underlying mechanisms of metastasis and chemoresistance are pressing issues in ovarian cancer therapy. Emerging evidence suggests that an endolysosomal Ca2+-permeable channel TRPML2 may contribute to cancer progression. However, its exact role and associated underlying mechanisms in ovarian cancer remain largely unknown.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that leads to sensory deficits, impaired balance, and a reduced quality of life (QoL). This study evaluates the effectiveness of sensorimotor and balance training compared with conventional physiotherapy.

Accurately predicting anticancer drug response is a central challenge in precision oncology. Existing computational methods, although valuable, often depend on pairwise molecular descriptors or limited graph-based encodings that cannot fully capture the complexity of molecular structures or their interactions with cellular states. These constraints hinder their robustness and generalization across diverse drugs and biological contexts, underscoring the need for more expressive frameworks.

Polypharmacology is dedicated to the development of compounds acting on at least two targets (multi-target-directed ligands, MTDLs). In 2025, the European Medicines Agency (EMA) approved 38 drugs, and 11 out of them were MTDLs. Most of them are antibody-drug conjugates, bispecific antibodies, or kinase inhibitors, all of which are indicated for tumor treatment, including datopotamab deruxtecan (hormone receptor-positive, HER2-negative breast cancer), tisotumab vedotin (advanced cervical carcinoma), linvoseltamab (fourth-line treatment of multiple myeloma), and erdafitinib (advanced urothelial carcinoma). The small molecule tiratricol is an orphan drug, which is indicated for the treatment of the very rare Allan-Herndon-Dudley syndrome. The second part of the present review is dedicated to the post-marketing safety surveillance of MTDLs approved by the EMA in 2022-2024. For 19 out of the 27 MTDLs, which are still available on the European market, comprehensive pharmacovigilance studies, mainly based on the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), were found. New safety signals have been identified, including Stevens-Johnson syndrome and progressive multifocal leukoencephalopathy. The analysis also revealed a more favorable safety profile of the MTDL tirzepatide (a dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide analogue) compared to the single-targeted drug semaglutide (glucagon-like peptide-1 analogue), including lower reporting rates of acute kidney injury and no significant suicidality signal.

Breast cancer remains a leading cause of cancer-related mortality among women, with prolonged exposure to endogenous estrogens recognized as a major risk factor. This study aimed to design, synthesize, and pharmacologically evaluate novel 3,3'-diindolylmethane (DIM) derivatives as multi-target modulators of estrogen-related pathways in breast cancer.

Gastric cancer is a highly prevalent malignancy of the digestive tract in China. Conventional chemotherapeutic drugs and human epidermal growth factor receptor 2 (HER2)‑targeted agents such as trastuzumab remain limited by significant challenges in the treatment of GC, including high rates of drug resistance, significant toxicity and adverse effects, and suboptimal tolerability. The advent of antibody-drug conjugates (ADCs) has marked a paradigm shift in the therapeutic landscape. This review systematically summarises the structural design, mechanisms of action, and current clinical applications of ADCs in HER2-positive or HER2-low advanced gastric cancer.

Cancer therapy-related cardiac dysfunction (CTRCD) remains a significant risk of contemporary cancer treatment. Despite advances in oncologic therapies, cardiac surveillance strategies have largely relied on uniform, intensive monitoring, often without consideration of individual cardiotoxicity risk. This review evaluates the rationale for transitioning from blanket surveillance to risk-based, personalized cardiac monitoring strategies, especially for HER2-targeted therapy.

In this study, we evaluated the in silico and in vitro anticancer activity of the antimicrobial peptide epinecidin-1 (Epi-1) and its lysine-substituted variants (Variant-1 (Var-1) & Variant-2 (Var-2)). Computational docking demonstrated energetically favourable and structurally consistent interactions between the peptides and cancer-associated receptors (MerTK (PDB ID: 7OLX), EphA3 (PDB ID: 2QO9), TGF-β receptor I/ ALK5 (PDB ID: 3TZM), TrkA / NTRK1 (PDB ID: 4AOJ), and progesterone receptor (PDB ID: 1A28)), with distinct binding orientations and interaction profiles observed across the variants. Molecular dynamics simulation further substantiated these findings by confirming the stability of the selected receptor-ligand complex, with consistent root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and intermolecular hydrogen-bond interactions profiles indicating sustained interaction integrity under dynamic conditions. The in vitro antiproliferative activity of Epi-1 and its variants was assessed by MTT assays against A549, HeLa, HepG2, IMR-32 and MCF-7 cell lines. Both variants exhibited a two- to four-fold increase in cytotoxic activity compared with native Epi-1. We also evaluated the combinational activity of each peptide with doxorubicin, where peptide-doxorubicin treatments resulted in effective cancer cell killing at reduced drug concentrations relative to individual treatments, the Var-2 + doxorubicin combination reduced cancer cell survival to below 10% at a combined concentration of 1 µg/mL (0.5 µg/mL peptide + 0.5 µg/mL doxorubicin), compared with ~ 30% survival in doxorubicin alone. This has been added alongside the existing two- to four-fold cytotoxicity enhancement of the variants over wild-type Epi-1, to better convey the impact of the synergistic response. While inducing selective lysis in cancer cells, the peptides exhibited minimal cytotoxicity toward non-cancerous HEK 293 cells, indicating improved therapeutic selectivity. DCFH-DA staining confirmed intracellular reactive oxygen species generation, and Acridine Orange/Ethidium Bromide (AO/EtBr) staining demonstrated apoptosis as the predominant mode of cell death across the cancer cell lines, although Var-1 induced necrotic death in HepG2 cells.

Epithelial cell adhesion molecule (EpCAM, CD326) is a transmembrane glycoprotein that plays important roles in both normal epithelial tissues and epithelial malignancies. Its frequent overexpression in several cancers, including pancreatic, colorectal, and prostate carcinomas, has made it an attractive therapeutic target. In this study, we designed and evaluated a novel EpCAM-binding diphtheria toxin fusion construct, DT-SNFYMPL, in which the EpCAM-binding peptide SNFYMPL was fused to a truncated diphtheria toxin. The recombinant construct was cloned, expressed in Escherichia coli BL21 cells, purified, refolded, and characterized in vitro. Structural modeling and validation predicted a stable three-dimensional structure for the designed protein. Binding analysis demonstrated interaction of DT-SNFYMPL with recombinant EpCAM in an ELISA-based assay. Cytotoxicity studies revealed dose- and time-dependent inhibition of MCF-7 and TC-1 cell proliferation, whereas no significant effect was observed in HUVEC cells under the conditions tested. DT-SNFYMPL also reduced the migration of cancer cells in Transwell assays; however, this effect is likely attributable, at least in part, to toxin-mediated cytotoxicity rather than direct inhibition of migratory pathways. Although the findings demonstrate biological activity of the DT-SNFYMPL construct and support its potential as an EpCAM-binding therapeutic candidate, the present study does not establish EpCAM-dependent internalization, receptor-mediated cytotoxicity, or therapeutic selectivity. Further mechanistic and preclinical studies are required to evaluate its mode of action, safety, and therapeutic potential in EpCAM-expressing malignancies.

Ovarian cancer remains a major clinical challenge, largely because many patients eventually develop resistance to cisplatin. In this study, gold nanoparticles (AuNPs) were synthesized using Artemisia chamaemelifolia extract through a green chemistry approach, and their antiproliferative activity was evaluated in cisplatin-resistant A2780cp ovarian cancer cells.

Therapy resistance is a complex and multifaceted pathological phenomenon, often driven by mutations in the p53 tumor suppressor gene. This ultimately causes tumor recurrence thereby adversely affecting patient prognosis. Therefore, development of effective chemotherapeutic agents that simultaneously inhibit tumor proliferation and overcome resistance mechanisms is of paramount importance. Recently, we identified Compound 4, a kinetically inert platinum-based antitumor agent capable of bypassing platinum resistance while exhibiting minimal nephrotoxicity. However, its potency in resistance scenario is still not investigated. Herein we evaluate the efficacy of Compound 4 against platinum-resistant cancers driven by mutant p53, using engineered p53-null ovarian (SKOV3) and gastric (KATOIII) cancer cell lines expressing hot-spot p53 mutants (p53mut) as well as patient derived tumor cells. While p53mut expressing cells showed differential sensitivity towards platinum, Compound 4 demonstrated superior cytotoxicity, regardless of p53 mutational status. This enhanced efficacy was attributed to its ability to induce a sustained DNA damage. This was further observed to be compounded by a deficiency in DNA repair responses failing to elicit an effective damage response. Additionally, Compound 4 induced significant mitochondrial depolarization which led to generation of persistent oxidative stress-like environment. Compound 4-mediated oxidative stress plays a crucial role in mediating its robust cytotoxic effects, as pharmacological quenching of reactive oxygen species (ROS) with an antioxidant markedly reduced cell death and gamma H2AX levels. Taken together, these results underscore the potential of Compound 4 as a potent agent capable of overcoming platinum resistance by targeting cancer cells irrespective of their p53 mutational status.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of antitumor immunity, capable of converting immunologically "cold" tumors into inflamed, immune-responsive states. Cyclic dinucleotide (CDN) agonists have clinically validated the impact of targeting this axis but are limited by poor pharmacokinetics, limited tumor penetration, and delivery challenges. Non-CDN based small-molecule modulators such as MSA-2 and amidobenzimidazole (ABZI) directly modulate cGAS-STING signaling. Beyond direct receptor agonism, coupling with metals offer platforms with complementary strategies to engage and amplify cGAS-STING signaling. Complexes incorporating platinum, ruthenium, iridium, rhodium, gold, copper, manganese, or zinc exploit redox activity, coordination versatility, and photophysical properties to induce nuclear or mitochondrial DNA stress, disrupt organelle homeostasis, and promote immunogenic cell death. By coupling STING activation to ferroptosis, pyroptosis, or cuproptosis, these complexes form the foundation of self-emerging design principles with elaborate mechanistic insights, and translational challenges shaping immune modulation for therapeutics.

Quadruple antiemetic prophylaxis with olanzapine (OLZ) is internationally recommended for cisplatin-based chemotherapy. However, OLZ is contraindicated by country-specific regulatory labeling in patients with diabetes mellitus (DM) in Japan due to concerns regarding hyperglycemia. This study aimed to evaluate the safety of short-term low-dose OLZ (≤10 mg) in patients with cancer and DM.

Gambogic acid (GA) shows potent inhibitory activity against various malignancies. However, achieving precise targeted delivery and spatiotemporal control of drug release at tumor sites remains a significant challenge. This study aimed to develop a hyaluronic acid (HA)-modified, redox-responsive drug delivery system based on a methoxy polyethylene glycol-linked GA prodrug (mPEG-ss-GA).

Melanoma is an aggressive type of skin cancer. Immune checkpoint inhibitors (ICIs): pembrolizumab, ipilimumab and/or nivolumab are recommended for the treatment of metastatic melanoma. ICIs enhance the immune response by blocking PD-1 and/or CTLA-4, improving remission and overall survival (OS). However, ICIs can cause immune-related adverse events (irAEs) such as colitis and dermatitis. Recent studies have demonstrated association between irAEs and improved tumour regression. This study aimed to evaluate the relationship between OS and stopping ICIs therapy due to immunological toxicity in metastatic melanoma patients. This study was approved by The University Hospitals Sussex NHS Foundation Trust (UHSussex) (reference 1963) and the University of Brighton (reference 2024-12,878-Shamsaldeen). Data collected from files of patients diagnosed with metastatic melanoma treated with ICIs at UHSussex between October 2011 to December 2022. In a total of 344 metastatic melanoma patients, the OS was 41.3%. There were 184 patients (53.5%) experienced irAEs. Among 202 patients who died by the cut-off point, there were 115 (56.9%) patients who did not experience irAE, while 68.3% of the 142 patients who were alive experienced irAE revealing overall association (p < 0.001, Pearson's R = 0.249) with logistics regression analysis showed association between irAE and OS (p < 0.001). Kaplan-Meier survival analysis showed significant longer OS (p < 0.001) for patients experienced irAE. Stopping ICIs due to toxicity reported in 83 patients from which 56 patients were alive by the cut-off point (67.5%) revealing overall association (p < 0.001, Pearson's R = 0.171) with logistics regression analysis showed association between stopping ICI due to toxicity and OS (p < 0.001). Kaplan-Meier survival analysis showed significant longer OS (p = 0.027) in patients whom their ICI therapy was stopped due to immune-related toxicity. In conclusion, the positive correlation between irAEs and survival may highlight the potential value of irAEs and irAE-related toxicity as biomarkers for therapeutic efficacy in advanced melanoma management.

The global spread of drug-resistant Plasmodium falciparum, particularly artemisinin-resistant strains, underscores the urgent need for novel antimalarial agents with distinct mechanisms of action and improved therapeutic potential. In this study, we employed an integrated in silico and in vitro strategy to identify compounds with inhibitory activity against P. falciparum apicoplast Gyrase B (PfGyrB). High-throughput virtual screening identified hit compounds with favorable predicted interactions against the target protein, which were subsequently evaluated using biochemical ATPase inhibition and parasite growth inhibition assays. UNC8153 and Fexofenadine hydrochloride demonstrated time-dependent antiplasmodial activity, with lower IC50 values at 96 h than at 48 h under prolonged exposure conditions. UNC8153 exhibited greater antiplasmodial activity (~25-fold) than the reference compound novobiocin during the second intraerythrocytic cycle. Morphological analysis indicated impaired parasite development during the second intraerythrocytic cycle under prolonged exposure conditions. Importantly, UNC8153 retained inhibitory activity against the artemisinin-resistant C580Y strain and exhibited minimal cytotoxicity toward HEK-293 cells under the tested experimental conditions. Structural similarity analysis indicated that the identified compounds are chemically distinct from currently used antimalarial drugs, supporting their structural novelty. Collectively, these findings identify UNC8153 as a structurally distinct new antiplasmodial scaffold warranting further mechanistic, pharmacological, and in vivo evaluation.

Accurate prediction of cancer drug responses is essential for advancing cancer treatment strategies and drug development. With the increasing availability of large-scale pharmacogenomic datasets, many deep learning models have been proposed to predict cancer drug responses. However, many existing models lack the capacity to offer critical biomedical insights, such as providing interpretability regarding the potential mechanism of action.

Brigatinib, an oral ALK inhibitor for metastatic NSCLC, lacks dosing guidance for special populations such as the Chinese. This study developed a physiologically based pharmacokinetic (PBPK) model using European data from patients with hepatic/renal impairment and drug-drug interaction (DDI) studies (itraconazole, rifampin). The model was then applied to predict (1) pharmacokinetics (PK) in the Chinese population; (2) PK in Chinese patients with hepatic/renal impairment; and (3) DDI in Chinese patients. Validated against clinical data, the model successfully predicted brigatinib PK alone and with CYP3A4 modulators. Food simulations showed a slight absorption delay without clinically meaningful exposure reduction. In hepatic/renal impairment, the model accurately predicted exposure changes across severity groups (fold error < 2). Extending the European-validated model to Chinese populations, the findings demonstrate reliable predictions of brigatinib PK in Chinese individuals as well as in Chinese patients with hepatic or renal impairment.

In this study, coumarin-3-carboxamide derivatives were designed and evaluated through a comprehensive in silico and in vitro combined approaches to identify cholinesterase inhibitors. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA analyses revealed strong binding affinities and stable interactions within key catalytic regions of AChE and BChE, with AChE-CM4 (ΔGbind = -60.27 ± 5.88 kcal/mol) and BChE-CM5 (ΔGbind = -54.95 ± 6.90 kcal/mol) emerging as the most promising complexes. ADME predictions indicated generally favorable pharmacokinetic profiles for the compounds; however, the predicted blood-brain barrier permeability levels were low to moderate. In vitro enzyme inhibition studies validated the computational results, showing that CM4 (IC50 = 19.04 ± 1.67 nM) and CM8 (IC50 = 17.73 ± 0.66 nM) exhibited significantly greater AChE inhibition than donepezil (IC50 = 27.27 ± 1.22 nM; p < 0.001), with CM3 (IC50 = 24.84 ± 1.99 nM) comparable to donepezil, while all derivatives (CM1-CM9) significantly outperformed tacrine against BChE (p < 0.001). Moreover, CM6 and CM9 inhibited colony formation in brain, breast, and colon cancer cell lines at concentrations below 5 µM. As a result, the alignment of computational and biological data highlights these coumarin-3-carboxamides as compelling lead candidates with both neuroprotective and anticancer potential for further pharmacological development.