Qishen Yiqi Dripping Pills (QSYQ) have shown promising therapeutic effects on cardiovascular diseases. Recent studies have reported their potential in mitigating doxorubicin-induced cardiotoxicity (DIC), but the primary active ingredients and specific mechanisms remain unclear. A total of 2740 differentially expressed genes (DEGs) were screened out. GSEA results were mainly enriched in Glycolysis, Apoptosis, Cellular Senescence, PI3K/Akt Signaling Pathway, TGF Beta Signaling Pathway, etc. Weighted gene co-expression network analysis yielded 1520 key module genes, and 1134 DIC-related genes were obtained by intersecting with DEGs. A total of 130 active ingredients and 943 target genes of QSYQ were obtained, and 50 common targets were identified after intersecting with DIC-related genes. The top 5 active ingredients were DFV, quercetin, Vestitone, formononetin and (6aR,11aR)-9,10-dimethoxy-6a,11a-dihydro-6H-benzofurano[3,2-c]chromen-3-ol. GO and KEGG enrichment analyses showed a close relationship with the HIF-1 signaling pathway and its upstream and downstream components. Three key genes identified were EP300, JUN, and CREBBP. Receiver operating characteristic analysis demonstrated good diagnostic value for these key genes, and their DOX-induced expression alterations were reversed by QSYQ (limited experimental evidence). Notably, the experimental validation of JUN showed a trend opposite to that observed in the bioinformatics analysis. Molecular docking revealed good binding capabilities of the primary active ingredients with the key genes. QSYQ may alleviate DIC through EP300, JUN, and CREBBP, providing new evidence for the use of QSYQ in ameliorating DIC.
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting factor and determinant of treatment continuation in patients receiving anticancer drugs. CIPN often persists even after treatment discontinuation and negatively impacts patients’ quality of life. At present, the risk factors for CIPN development remain unclear. This study aimed to exploratively examine the association between genetic polymorphisms and CIPN in Japanese patients with metastatic pancreatic cancer treated with gemcitabine and nab-paclitaxel (GnP) as first-line chemotherapy. This exploratory analysis of the GENESECT dataset included 65 patients with metastatic pancreatic cancer who received GnP therapy. The association of 14 genetic polymorphisms with CIPN was analyzed by multivariate Firth logistic regression with Benjamini–Hochberg correction for multiple comparisons. The Kaplan–Meier curves among genetic polymorphisms were analyzed using log-rank test to compare the cumulative dosage of nab-paclitaxel until CIPN ≥ grade 2. Results were considered significant at p < 0.05. The AA and AC variants of LGALS3 rs4652 tended to be associated with CIPN ≥ grade 2 (adjusted odds ratio (OR), 0.248; 95
Cemiplimab is a fully human PD-1 inhibitor approved for cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer. Post-market safety surveillance is essential given the broad and evolving indications for immune checkpoint inhibitors. All FAERS reports with cemiplimab as the primary suspect drug were extracted. Proportional Reporting Ratios (PRR), Reporting Odds Ratios (ROR), and chi-squared statistics were calculated for each adverse event. Disproportionality signals were defined by PRR >= 2, chi-squared >= 3.841, and a minimum of 15 reports. A total of 1,460 cemiplimab reports were identified in the FAERS database. Twenty-two adverse events met all signal detection criteria. The strongest signals were observed for myocarditis (PRR 54.35, n = 40), myositis (PRR 46.10, n = 25), pemphigoid (PRR 36.06, n = 16), and pneumonitis (PRR 19.37, n = 31). Immune-mediated adverse events predominated, consistent with the mechanism of PD-1 blockade. FAERS disproportionality analysis identifies a signal profile for cemiplimab dominated by immune-related adverse events across cardiac, pulmonary, dermatologic, and endocrine systems. These findings are consistent with the known immunotoxicity of PD-1 inhibitors and support heightened clinical vigilance for myocarditis and immune-mediated pneumonitis.
Kinase inhibitors are commonly used in research and clinical practice. Among them, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as afatinib and osimertinib, constitute an important subclass. The aim of this study was to create an irreversible covalent EGFR TKI exhibiting endogenous fluorescence, i.e., intrinsic fluorescence without the need for additional fluorochromes. These compounds, designated SQI-2, SLT40, and SLT41, were successfully developed and shown to effectively inhibit the EGFR, EGFRL858R/T790M, and EGFRvIII kinases. The developed compounds are suitable for a range of cytochemical analyses, including real-time assays. The proposed TKIs may serve as research and diagnostic tools and represent precursors of new types of therapeutic compounds.
Despite advances in new therapies, multiple myeloma (MM) remains incurable with most patients relapsing or becoming refractory to treatment demonstrating the need for novel therapeutic strategies. We previously identified VP79s, a novel guanidinium-based compound, with potent anti-myeloma activity which targets the dysregulated IL-6/JAK/STAT signalling pathway. Here, we aim to further evaluate the translational potential of VP79s by examining whether it synergises with the BH3 mimetic venetoclax and exploring the mechanisms underlying this effect. The pro-apoptotic effect of VP79s and venetoclax alone or in combination was assessed by annexin V/propidium iodide staining followed by flow cytometry analysis. Western blotting was performed to evaluate the expression level of key pro- and anti-apoptotic members of the Bcl-2 family. BH3 profiling assessed apoptotic priming of cells to a Bim-domain peptide. Co-treatment of NCI-H929 and MM1.S cells with VP79s/venetoclax resulted in a synergistic enhancement of apoptosis which correlated with a decrease in anti-apoptotic Mcl-1 and concurrent increase in pro-apoptotic Bim S. Synergy was not observed in U266B1 cells possibly because these cells demonstrated relative resistance to venetoclax and exhibited a lower level of apoptotic priming in response to a Bim peptide. Importantly, co-treatment of NCI-H929 cells with VP79s and venetoclax was shown to overcome bone marrow stromal cell induced drug resistance. Preliminary findings also indicate that the combination treatment induced an enhanced reduction in viability of ex vivo myeloma patient samples with minimal cytotoxicity toward healthy donor lymphocytes observed. These findings support further preclinical investigation of VP79s in combination with venetoclax as a potential therapeutic strategy in MM.
Pegenzileukin (SAR444245) is a pegylated recombinant human IL-2 variant designed to expand effector T cells and NK cells without stimulating regulatory T cells. This study evaluated pegenzileukin with pembrolizumab or cetuximab for treating advanced gastrointestinal cancers. A total of 138 patients with advanced gastric cancer (GC), colorectal carcinoma, esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC) were enrolled across seven cohorts in this phase 2 study. Patients received pegenzileukin (24 µg/kg every 3 weeks [Q3W]) with pembrolizumab (200 mg Q3W) or cetuximab (initially 400 mg/m2 and then 250 mg/m2 weekly). The primary endpoint was the objective response rate (ORR). The secondary endpoints were time to response, response duration, clinical benefit rate, progression-free survival (PFS), and safety. Exploratory biomarker analyses assessed immune cell expansion and cytokine levels. The ORR varied across the cohorts, with the highest in ESCC cohort (1/5; 20.0
Lazertinib is a third-generation, brain-penetrant, mutant-selective EGFR tyrosine kinase inhibitor approved for first-line treatment of EGFR-mutated non-small cell lung cancer, including in combination with amivantamab. Post-market safety surveillance is important given its recent approval and evolving real-world use. All FAERS reports with lazertinib as the primary suspect drug were extracted. Proportional Reporting Ratios (PRR), Reporting Odds Ratios (ROR), and chi-squared statistics were calculated for each adverse event. Disproportionality signals were defined by PRR ≥ 2, chi-squared ≥ 3.841, and a minimum of 3 reports. A total of 141 lazertinib reports were identified in the FAERS database. Twenty-six adverse events met all signal detection criteria. The strongest signals were observed for paronychia (PRR 132.90, n = 3), dermatitis acneiform (PRR 118.59, n = 4), peripheral sensory neuropathy (PRR 91.97, n = 3), and peripheral neuropathy (PRR 50.09, n = 28). Dermatologic and neurologic adverse events predominated, consistent with the mechanism of EGFR inhibition. FAERS disproportionality analysis identifies a signal profile for lazertinib dominated by EGFR inhibitor-class dermatologic and neurologic toxicities, alongside an infusion-related reaction signal reflecting combination use with amivantamab. The modest report volume warrants cautious interpretation; however, the signal patterns are mechanistically coherent and consistent with the known toxicity profile of third-generation EGFR TKIs.
Fulminant type 1 diabetes (FT1D) is a rare immune-related adverse event associated with nivolumab, and its clinical characteristics remain unclear. This study aims to characterize the clinical features of nivolumab-associated FT1D and to generate evidence to inform its diagnosis and prevention. A systematic search of databases was conducted to identify clinical cases of nivolumab-associated FT1D reported through March 31, 2026. Clinical data for the patients were extracted and subjected to statistical analysis. A total of 59 patients were included, with a median age of 59 years (range 22, 87). The median time to onset of FT1D was 90 days (range 9, 1988) after the initial administration of nivolumab, with a median treatment cycle of 6 cycles (range 1, 136). Polyuria (45.1
Leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading death cause, with extramedullary disease history as an independent relapse risk factor in acute leukemia. We analyzed 10 patients with extramedullary disease history who received allo-HSCT with mitoxantrone liposome (Lipo-MIT)–containing conditioning at our center (Dec 2022–Jan 2025). Median age was 39.5 (14–63), 7 had acute myeloid leukemia (AML, including myeloid sarcoma), 2 T lymphoblastic lymphoma/leukemia, and 1 B-cell acute lymphoblastic leukemia. Pre-transplant, 4 were in complete remission (CR) (1 with minimal residual disease [MRD] positivity) and 6 had residual lesions (2 with BM blasts ≥ 5
A common, often unstated paradigm in T-cell engager (TCE) translation assumes that target-antigen density and drug exposure are the main efficacy drivers, with effector context secondary. This paradigm is visible in dose-escalation strategies and in the use of high-E:T screens as principal preclinical assays. We tested whether an alternative, receptor-saturation framework better organizes the published AMG 330 record in acute myeloid leukemia (AML). Receptor-saturation arguments motivate two qualitative expectations: at sufficiently high CD33 densities, EC _50 should show little systematic dependence on additional antigen density, and response should become increasingly constrained by effector availability and functional state. We tested these expectations using two statistical reanalyses of published AMG 330 data—log-linear regression of EC _50 on CD33 density across 11 AML cell lines, and a comparative effect-size analysis of effector-to-target (E:T) ratio versus CD33 expression in 38 primary AML samples—integrated with clinical exposure-response findings and effector-augmenting rescue studies. Both expectations were supported. CD33 density did not significantly predict EC _50 across the 3.9-fold range tested ( p=0.13 ; bootstrap 95 p=0.7 , not significant). Clinical exposure-response analyses identified baseline E:T ratio and T-cell PD-1 expression as response correlates. A similar target-effector dissociation has been reported in several other TCE programs. The AMG 330 record is more coherently organized by an effector-context framework than by the conventional target-density-and-exposure paradigm. These findings indicate that endogenous-effector assays, paired target-effector biomarkers, and rational effector-support strategies are likely to be clinically informative complements to conventional cell-line potency and dose-escalation approaches in future CD33 TCE development.
DS-1471a is a humanized antibody that targets CD147, a transmembrane glycoprotein frequently overexpressed in cancer cells, and has undergone a phase 1 clinical study for advanced solid tumors. To further investigate DS-1471a’s therapeutic potential and the underlying molecular mechanisms involved, we examined its efficacy in patient-derived xenograft (PDX) models of liver cancer. DS-1471a exhibited potent antitumor effects in multiple PDX models, with positive correlations observed between DS-1471a efficacy and expression of CD147 and related proteins such as SMAD4, ARF6, and FBXO22. Among these proteins, overexpression of FBXO22, a ubiquitin ligase, enhanced DS-1471a efficacy in liver cancer xenograft models. Mechanistic analysis showed that FBXO22 overexpression was associated with reduced expression of p21/CDKN1A, a cyclin-dependent kinase inhibitor previously characterized as a degradation target of FBXO22, suggesting a potential regulatory relationship between these proteins. Moreover, in tumor models lacking p21, DS-1471a efficacy was also enhanced, whereas DS-1471a-resistant tumors expressed higher levels of p21 protein. Although direct causal relationships remain to be fully established, these results suggest possible mechanisms underlying DS-1471a efficacy involving not only CD147 expression but also FBXO22 and p21. Taken together, these preclinical findings indicate a potential clinical benefit of DS-1471a and provide useful mechanistic insights for liver cancer treatment.
B7-H4 is overexpressed in various cancers, making it a promising target for cancer immunotherapy. This phase 1, open-label, first-in-human study in patients with advanced/metastatic breast, ovarian and endometrial cancer evaluates the safety, pharmacokinetics (PK), and anti-tumour activity of PF-07260437, a novel B7-H4xCD3 bispecific T-cell engager. Enrolled patients received escalating doses of PF-07260437 (with/without priming dose) subcutaneously every two weeks, with a starting dose of 100 µg. Primary objectives included determination of maximum tolerated dose (MTD)/recommended dose for expansion (RDE), safety and tolerability. Secondary objectives included PK parameters and immunogenicity. Bayesian logistic regression model (BLRM) was used to guide dose escalation. Thirty patients with advanced/metastatic breast, ovarian and endometrial cancer received the study treatment during dose escalation; all were female (median age, 61.0 [41–75] years). Four patients (13.3
KRAS-mutant NSCLC resistance to MEK inhibitors (MEKi) is related to compensatory upregulation of fibroblast growth factor receptor (FGFR) signaling. Futibatinib is a potent, covalent FGFR1–4 inhibitor approved for locally advanced/metastatic cholangiocarcinoma with FGFR2 fusions. We conducted a bench-to-bedside study evaluating futibatinib plus the MEKi binimetinib preclinically, followed by a Phase Ib trial of patients with advanced cancer. The effect of futibatinib ± MEKi on cell signaling and proliferation of KRASmt NSCLC lines (A549, LU99) were assessed in vitro. In a Phase Ib study, patients with advanced cancer who had exhausted standard therapies received futibatinib QD plus binimetinib BID orally following a “3 + 3” dose-escalation design. Primary objective was to establish the recommended Phase 2 dose (RP2D) based on safety. Secondary endpoints included pharmacokinetics and anti-tumor activity. In vitro, MEKi with futibatinib resulted in additive or synergistic anti-tumor activity in KRASmt NSCLC lines. Twenty-three patients received futibatinib with binimetinib at 4 dose levels. The most prevalent adverse events were reversible retinopathies in 20 patients, including 2 DLTs and limiting dose escalation beyond futibatinib 16 mg QD plus binimetinib 15 mg BID (MTD). There were no relevant drug-drug interactions between binimetinib and futibatinib. One patient harboring an FGFR2 fusion had a partial response. No RP2D could be defined as the MTD was below active dose levels of binimetinib. Despite additive anti-tumor activity for FGFR and MEK inhibition in KRASmt NSCLC lines, the trial was stopped after dose escalation, as no RP2D was identified for futibatinib/binimetinib due to reversible retinopathies. Trial register number. NCT04965818. Trial registration date. 20-September-2021.
Interleukin-23 (IL23) has been reported to drive androgen receptor (AR) and JAK2-STAT3 signaling, promoting treatment resistance and disease progression in advanced prostate cancer (PC). We evaluated the safety, tolerability, and antitumor activity of the anti-IL23 monoclonal antibody tildrakizumab in combination with the AR pathway inhibitor (ARPI) abiraterone acetate (AA) in men with ARPI-resistant metastatic castration-resistant PC (mCRPC). mCRPC patients of ECOG performance status (PS) ≤ 2, who had previously progressed on first-line ARPI therapy, were treated with tildrakizumab (100 mg, 300 mg, 600 mg; 4-weekly) in combination with AA (YonsaTM, 500 mg daily). The primary objective was to determine the recommended phase 2 dose. Secondary endpoints were elucidation of pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. No dose limiting toxicities (DLTs) were observed, nor any grade ≥ 3 adverse effects (AEs). The most common treatment-related AEs attributable to tildrakizumab were grade 1—2 fatigue (n = 3/12; 25.0
Lurbinectedin in combination with irinotecan showed synergistic antitumor activity in preclinical studies. A phase I/II trial (NCT02611024) evaluated this combination in patients with advanced solid tumors. The phase II stage evaluated the antitumor activity of the recommended dose (RD) (lurbinectedin 2.0 mg/m2 on Day (D)1 plus irinotecan 75 mg/m2 on D1 and D8 q3wk with primary granulocyte colony-stimulating factor prophylaxis) in five tumor-specific cohorts. This pooled analysis describes the safety profile of this combination from 233 patients with different advanced solid tumors treated at the RD. Adverse events (AEs) and laboratory abnormalities were graded using NCI-CTCAE v.4. The most frequent AEs (any grade) related to treatment were fatigue (71
Newly approved kinase inhibitors (2024–2025) have limited post-approval safety data. We developed a weighted ToxPi framework to prioritize multi-endpoint liabilities spanning hERG cardiotoxicity, DILI, Ames genotoxicity, and CYP3A4-mediated drug-drug interaction potential. Thirteen compounds (12 KIs approved in 2024–2025 plus imatinib as a historical reference anchor) were profiled using ADMETlab 3.0, vNN-ADMET, and SwissADME (formula inputs) and integrated into a weighted composite (wToxPi = 0.30 × hERG + 0.30 × DILI + 0.20 × Ames + 0.20 × CYP3A4). Robustness was assessed across weighting schemes and sensitivity analyses addressing fusion-recoding scenarios, CYP3A4 platform asymmetry, and combination-regimen confounding. DILI signal saturation dominated the cohort: 12 of 13 compounds showed DILIcon ≥ 0.80, limiting hepatic discrimination and shifting differentiation to hERG and Ames variability. Sevabertinib (0.860), Zongertinib (0.840), and Lazertinib (0.775) ranked highest, whereas Mirdametinib (0.080) was the structural outlier. Ranking remained stable: ADMETlab-only and thresholded majority-vote alternatives preserved the principal structure (Spearman ρ = 0.780 and 0.812), whereas soft-label pseudo-probability mapping showed near-identity concordance (ρ = 0.978); a broader sensitivity grid (p = 0.60–0.90) confirmed structural stability (ρ = 0.929–0.995). Exploratory FAERS findings provided supportive post-marketing context. This framework provides transparent, reproducible, hypothesis-generating prioritization of newly approved KIs. Class-level DILI saturation reinforces the need for close hepatic surveillance in pharmacovigilance interpretation regardless of composite rank; hERG and Ames provide the main inter-compound discriminatory signal. Sevabertinib, Zongertinib, and Lazertinib ranked highest, whereas Mirdametinib was the structural outlier; for Inavolisib and Tovorafenib, endpoint-specific hepatic surveillance remains warranted irrespective of composite rank. The model should support pharmacovigilance prioritization rather than replace clinical monitoring or individualized risk assessment.
The hedgehog (Hh) signalling pathway is aberrantly activated in solid tumours. Inhibition of Hh signalling by SMO inhibitors is effective in the treatment of basal cell carcinomas and medulloblastomas whereas combination treatments may be required in other solid tumours. When given with an SMO inhibitor in preclinical models, the efficacy of paclitaxel is enhanced and there is potential reversal of mechanisms of resistance to paclitaxel supporting clinical investigation of the combination. In this phase I trial, the safety and feasibility of the oral SMO inhibitor, taladegib, was evaluated in combination with weekly paclitaxel in patients with advanced solid tumours. This was an open-label, nonrandomised, multicentre, dose escalation trial using a standard 3 + 3 design (EudraCT: 2014-004695-37 ISRCTN15903698). Primary objectives were to determine dose-limiting toxicities and the maximum tolerated dose of the combination. Patients received up to 6 cycles of paclitaxel 80 mg/m2 (day 1, 8 and 15 of a 28-day cycle). Then, 16 patients were recruited into 3 cohorts and received taladegib at 100 mg, 200 mg and 400 mg once daily, respectively. Grade 2/3 peripheral sensory neuropathy was the dose-limiting toxicity. The maximum tolerated dose of taladegib in combination with weekly paclitaxel was 200 mg once daily. Four patients had a partial response and 4 had confirmed stable disease at 16 weeks. The combination is feasible but cumulative neuropathy may limit longer term treatment. Hh signalling may be implicated in chemotherapy-induced neuropathy.
The MAX (MYC-associated protein X) was discovered as an obligate heterodimer of MYC, a protein product of a prolific proto-oncogene that is dysregulated in over three-fourths of cancers. Targeting MYC directly is fraught with challenges due to the disordered structure of the MYC protein that is not conducive for small molecule inhibitor design. Therefore, the MYC/MAX protein-protein interaction provides an opportunity for indirect targeting of MYC. We compared the efficacy of first- and second-generation MYC/MAX small molecular inhibitors, 10,058-F4 and 3jc48-3 respectively, and tested the novel class of proteomimetic MYC/MAX inhibitor JKY-2-169 on inhibiting growth of human prostate cancer cell line DU145 in 2D culture. In addition, we validated the efficacy of inhibitors using 3-dimensional (3D) systems: 3D microcapsules and human prostate cancer spheroids generated by harvesting fresh cancerous tissue from human radical prostatectomy surgical specimens. Treatment in both 3D models showed that 3jc48-3 and JKY-2-169 reduced cell viability. Analysis of patient-derived spheroids before and after treatment showed that spheroid growth increased significantly over time only in the DMSO control group, while inhibitor-treated spheroids did not show significant growth during the same period; among the treatment groups, only 3jc48-3 significantly reduced spheroid size compared with the DMSO control. The results suggest that the proteomimetic and second-generation MYC inhibitors suppress cell growth at lower concentrations compared to the first-generation inhibitors. Comparative proteomic analysis of treated and untreated DU145 cells, based on a pre-defined twofold expression threshold, identified common cellular pathways altered by MYC/MAX inhibition primarily involving cytoskeletal organizations, cell cycle regulation, metabolism, and RNA-related functions. This study provides promising preliminary in vitro support for further investigation and development of novel MYC inhibitors.
