To compare the efficacy and safety of different Claudin (CLDN)18.2-directed regimens in advanced gastric/gastroesophageal junction adenocarcinoma. PubMed, Web of Science, CNKI, and Wanfang databases were searched up to June 2026. Single-arm trials evaluating CLDN18.2-targeted gastric/gastroesophageal junction adenocarcinoma therapies were included. Meta-analysis was performed to pool objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and safety outcomes. Ten studies (710 patients) were included. The pooled mPFS was 4.19 months (95
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
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
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.
