Imatinib remains a mainstay of treatment for gastrointestinal stromal tumors (GISTs), yet responses may be incomplete or short-lived. We examined whether parthenolide (PTL) enhances imatinib activity in GIST models and characterized the cellular changes associated with combined treatment. Public GIST transcriptomic datasets were analyzed as hypothesis-generating resources. GIST-T1 and GIST-882 cells were treated with PTL, imatinib, or their combination. Cell growth, migration, colony formation, apoptosis, reactive oxygen species, mitochondrial function and ultrastructure, ER-stress-associated proteins, and autophagy-associated markers were assessed. Antitumor activity was further examined in a GIST-T1 xenograft model. PTL and imatinib each inhibited GIST cell growth in a concentration-dependent manner. At the selected concentrations, the combination produced greater and more sustained suppression of cell viability, migration, and colony formation than either monotherapy. TUNEL staining and Annexin V-FITC/PI analysis showed increased apoptosis, accompanied by lower Bcl-2 expression and a higher Bax/Bcl-2 ratio. Combined treatment also increased DCF fluorescence, reduced mitochondrial membrane potential, caused mitochondrial ultrastructural abnormalities, increased p-IRE1α/IRE1α and CHOP, and altered PINK1, LC3B, and Beclin-1. In vivo, the combination showed the slowest mean tumor growth and the lowest endpoint tumor weight, without greater body weight loss than imatinib alone. PTL enhanced imatinib activity in imatinib-responsive GIST models. This effect was accompanied by apoptotic, oxidative, mitochondrial, ER stress-associated, and autophagy-associated changes; however, their causal relationships remain to be established.

DT-9081 is a selective antagonist of the prostaglandin E2 receptor EP4, developed to counteract tumor-driven immunosuppression. This first-in-human phase I study aimed at determining the dose-limiting toxicity/maximum tolerated dose (DLT/MTD) of DT-9081 and identifying the recommended phase II dose (RP2D) in patients with advanced solid tumors. This open-label, dose-escalation study enrolled patients with advanced (unresectable, recurrent or metastatic) solid tumors refractory to standard therapies. DT-9081 was administered orally once daily across six sequential dose cohorts (25-600 mg, daily). Primary objectives were safety and determination of the RP2D. Secondary objectives included efficacy, pharmacokinetics (PK) characterization, and pharmacodynamic (PD) assessment. Twenty-nine patients were treated. One dose-limiting toxicity (grade 3 increased hepatic enzymes) was observed at the 50 mg dose level. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (55.2%), decreased appetite (24.1%), nausea (20.7%), vomiting (20.7%), and asthenia (20.7%). Most TEAEs were grade 1-2. Grade ≥ 3 DT-9081-related adverse events occurred in 2 (6.9%) patients (grade 3 diarrhea and grade 3 increased hepatic enzymes). DT-9081 exhibited dose-proportional PK with sustained plasma exposure exceeding preclinical IC50 thresholds at higher dose levels. Pharmacodynamic analyses demonstrated dose-dependent reversal of EP4-mediated suppression of TNF-α production, confirming target engagement. Based on integrated safety, PK, and PD data, 600 mg once daily was selected as the RP2D, despite the absence of meaningful clinical activity. MTD was not reached and pharmacodynamic activity was consistent with EP4R antagonism. These findings support further clinical development of DT-9081, including evaluation in immunotherapy-based combination regimens.EUCT Number: 2024-516206-28-00;NCT05582850.Study registration date: 10/10/2022.

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% confidence interval (CI), 0.055-1.02, p = 0.053), and a cumulative dose of nab-paclitaxel ≥ 1625 mg/m[2] (median) was significantly associated (adjusted OR, 6.72; 95% CI, 2.02-27.0, p = 0.002). Patients with AA and AC variants of LGALS3 rs4652 tended to have larger median cumulative dosages of nab-paclitaxel until the development of CIPN ≥ grade 2 (4050 mg/m[2] vs. 1600 mg/m[2], p = 0.073). LGALS3 rs4652 may represent a promising candidate biomarker that requires prospective validation.

RET rearrangements and activating point mutations are major oncogenic drivers in thyroid cancer. Although selective RET inhibitors such as selpercatinib (LOXO-292) and pralsetinib (BLU-667) induce significant clinical responses, adaptive resistance frequently arises through reactivation of MAPK signaling. The molecular mechanisms underlying sustained ERK activation in residual RET-mutated thyroid cancer cells remain incompletely defined. Here, we investigated whether SHP2 mediates adaptive ERK reactivation following RET inhibition. RET-mutated thyroid cancer cell lines (TPC-1 and TT) were treated with selective RET inhibitors alone or in combination with the SHP2 inhibitor SHP099. RET inhibition initially suppressed ERK phosphorylation and was followed by compensatory transcriptional upregulation of multiple receptor tyrosine kinases, including MET, EGFR, FGFR2, and PDGFRB, together with ERK reactivation. Pharmacologic inhibition or knockdown of SHP2 attenuated this adaptive MAPK response and sustained ERK suppression. Combined targeting of RET and SHP2 significantly reduced cell proliferation in vitro and produced marked tumor growth inhibition in a TPC-1 xenograft model without significant loss of body weight. These findings support SHP2 as an important mediator of adaptive ERK reactivation following RET inhibition. Dual blockade of RET and SHP2 produces more durable MAPK pathway suppression and enhances antitumor efficacy in the models tested, providing a rationale for further evaluation of this combination in RET-altered thyroid cancer.

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, EGFR[L858R/T790M], and EGFR[vIII] 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.

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.

LP-184 is a novel acylfulvene pro-drug that alkylates DNA after bioactivation by the intracellular oxidoreductase prostaglandin reductase 1 (PTGR1). In preclinical studies, potent growth inhibition has been observed against a wide variety of solid tumor models, particularly those carrying DNA damage repair deficiency. Here, we report results of the first-in-human dose escalation trial of LP-184 in advanced solid tumors. A dose escalation Bayesian optimal interval design was used with a starting dose of 0.01 mg/kg. Eligible patients with advanced refractory solid tumors were enrolled to receive LP-184 intravenously on days 1 and 8 of each 21-day cycle. Sixty-three patients were enrolled, with a median age of 62 years. Twelve dose levels (DLs) were evaluated with one dose-limiting toxicity (DLT) at DL11 (0.49 mg/kg; grade 4 platelet count decreased) and two DLTs at DL12 (0.61 mg/kg; grade 3 alanine aminotransferase increased and acute liver injury). The most common (≥ 20%) treatment-related adverse events of any grade included nausea, vomiting, fatigue, and platelet count decreased. No treatment-related deaths occurred during the study. Best response to monotherapy LP-184 was stable disease (SD), which was observed in 22 (40%) of the evaluable patients. Three patients experienced SD that lasted more than 12 months. LP-184 was safe and tolerable in the Phase 1a trial in patients with advanced refractory solid tumors. The maximum tolerated dose (MTD) of LP-184 is 0.49 mg/kg. Registry: ClinicalTrials.gov, TRN: NCT05933265, Registration date: June 23, 2023.

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/m[2] and then 250 mg/m[2] 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%) and the lowest in GC Cohort 2 and the HCC cohort (1/19; 5.3% and 1/20; 5.0%, respectively). The median PFS was consistent across the cohorts (1.9-2.1 months). The most common treatment-emergent adverse events were asthenia (Pegenzileukin + pembrolizumab) and infusion-related reactions (Pegenzileukin + cetuximab). The biomarker analyses demonstrated robust expansion of CD8[+] T cells, CD8[+] Ki67[+] T cells, NK cells, and NK Ki67[+] cells without significant modulation of regulatory T cells. Pegenzileukin with pembrolizumab or cetuximab demonstrated limited efficacy, with a manageable safety profile in advanced GI cancers. The biomarker data supported the mechanism of action involving the upregulation of CD8[+] T cells and NK cells. ClinicalTrials.gov Identifier: NCT05104567.

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.

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%), polydipsia (31.4%), weight loss (29.4%), thirst (23.5%), nausea (23.5%), vomiting (21.6%), and fatigue (19.6%) were the main symptoms. The median plasma glucose level at the diagnosis of FT1D was 594 mg/dL (range 208.8, 1652.4), and the median HbA1c was 7.2% (range 5.4, 8.9). Glutamic acid decarboxylase antibody positivity was detected in 23.6% of patients. Following nivolumab discontinuation and initiation of intensive insulin therapy, glycemic control was satisfactorily achieved. FT1D is a rare immune-related adverse event associated with nivolumab. Close plasma glucose monitoring should be maintained both during nivolumab therapy and after drug discontinuation. The possibility of FT1D should be considered in patients presenting with hyperglycemic symptoms and diabetic ketoacidosis. Nivolumab-associated FT1D requires long-term maintenance insulin therapy.

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%, 2 with MRD positivity). The conditioning regimen was Lipo-MIT + total body irradiation/busulfan + cyclophosphamide ± cytarabine, with a median Lipo-MIT dose of 26.1 (18.5-28.9) mg/m[2]. Mucosal injury showed a high incidence (9/10) after conditioning, but most were transient and controllable with supportive care. Engraftment succeeded in 9 patients, with a median neutrophil recovery time of 16 (11-21) days and platelet recovery time of 20 (11-39) days. Only 1 patient developed grade 2 skin acute graft-versus-host disease (aGVHD). All 9 engrafted patients achieved complete remission (CR) post-transplantation; one had MRD positivity at + 177 days, which turned negative after chemotherapy combined with donor lymphocyte infusion. One patient relapsed at + 234 days and died at + 272 days. The patient with engraftment failure died at + 346 days due to disease progression, with a history of polycythemia vera complicated by myelofibrosis. Lipo-MIT conditioning shows promising efficacy/safety for allo-HSCT in extramedullary disease patients. Randomized trials are needed.