bims-midomi 2026-03-08 papers

Future Oncol. 2026 Mar 07. 1-13

POIESIS: a phase III study of add-on navtemadlin in JAK inhibitor-naïve myelofibrosis patients with a suboptimal response to ruxolitinib.

Pankit Vachhani, Abdulraheem Yacoub, Raajit Rampal, Terrence Bradley, Claire Harrison, Tania Jain, Andrew Kuykendall, Francesca Palandri, John Mascarenhas, Haifa Al-Ali, Francesco Passamonti, Wayne Rothbaum, Srdan Verstovsek, Florian H Heidel.

Most myelofibrosis (MF) patients treated with ruxolitinib fail to achieve optimal response (i.e., spleen volume reduction ≥35% [SVR35] and improvement in total symptom score ≥50% [TSS50], and instead experience suboptimal reductions in spleen volume and constitutional symptoms. Maximizing SVR and TSS is critical for MF patients, as both are associated with improved quality of life (QoL) and overall survival (OS). Navtemadlin is a potent, selective, oral MDM2 inhibitor that restores p53 activity, inducing apoptosis of malignant TP53 wild-type (TP53WT) CD34+ MF progenitor cells. In vitro and clinical data demonstrated navtemadlin's synergy with ruxolitinib and disease-modifying potential. POIESIS is a global, randomized, double-blind phase III trial (NCT06479135) evaluating navtemadlin versus placebo as add-on to ruxolitinib in JAK inhibitor-naïve TP53WT MF patients with suboptimal response to ruxolitinib. The study includes a ruxolitinib monotherapy run-in period, followed by randomization of suboptimal responders to add-on navtemadlin or placebo to their stable ruxolitinib dose. Study objectives are to isolate the contribution of add-on navtemadlin by assessing SVR and TSS 24-weeks after randomization from the pre-randomization baseline and to demonstrate that this contribution is clinically meaningful using established SVR and TSS endpoints from the pre-ruxolitinib treatment baseline. Secondary endpoints include progression-free survival, leukemia-free survival, and OS.Clinical Trial Registration: NCT06479135 (ClinicalTrials.gov); EUCT 2023-504724-25-00 (EUClinicalTrials.EU).

Keywords: JAK inhibitor-naïve; MDM2 inhibitor; Myelofibrosis; navtemadlin; p53; phase III POIESIS trial; spleen volume reduction; suboptimal response

DOI: https://doi.org/10.1080/14796694.2026.2638989

J Ethnopharmacol. 2026 Mar 02. pii: S0378-8741(26)00311-9. [Epub ahead of print] 121460

Aloperine exerts anti-ovarian cancer effects by regulating the tricarboxylic acid cycle and glycolysis: A comprehensive study integrating network pharmacology, molecular docking, metabolomics, and experimental validation.

Dan Zhang, Qianrui Yang, Huidong Xia, Qiaohong Jiang, Jianmin Sun, Ru Bai.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloperine (ALO), an alkaloid derived from Sophora alopecuroides L., demonstrates therapeutic potential against malignant tumors, while the role of ALO and its molecular mechanisms in ovarian cancer remain unclear.
AIM OF THE STUDY: This study aims to systematically investigate the efficacy and molecular mechanisms of ALO against ovarian cancer by integrating network pharmacology and metabolomics.
MATERIALS AND METHODS: The anti-tumor effect of ALO on ovarian cancer cells was evaluated using CCK-8, colony formation, cell scratch and transwell invasion assay in vitro. An ovarian cancer xenograft mouse model was used to evaluate the anti-ovarian cancer effect of ALO in vivo. Potential targets of ALO in ovarian cancer were predicted via network pharmacology, and the binding affinity of ALO to the potential targets was analyzed using molecular docking techniques. High-performance liquid chromatography-mass spectrometry (HPLC-MS) was used to identify the different metabolites of ALO and their metabolic pathways in ovarian cancer cells, followed by multi-level integrated analysis of network pharmacology and metabolomics results. Metabolite detection kits, western blotting, and qPCR were employed to validate the involved metabolites and their associated target genes.
RESULTS: ALO suppressed the proliferation, migration and invasion of ovarian cancer cells SKOV-3 and ES-2 in a dose dependent manner in vitro. Correspondingly, ALO inhibited the growth of ovarian cancer xenografts in vivo. Network pharmacology and molecular docking analysis revealed Mouse double minute 2 homolog (MDM2), Janus kinase 2 (JAK2), Cyclin-dependent kinase 2 (CDK2), Myeloperoxidase (MPO), Janus kinase 1(JAK1) and Androgen receptor (AR) as the potential targets of ALO in ovarian cancer. While metabolomics analysis showed that ALO increases citrate acid and α-ketoglutarate (α-KG) levels in ovarian cancer cells. The integrated metabolomics, network pharmacology, and molecular docking identified that ALO primarily affects the tricarboxylic acid cycle (TCA cycle) and three hub genes, including MDM2, JAK2, and CDK2. In the experimental validation, ALO treatment increased the levels of key metabolites citrate acid and α-KG in the TCA cycle in ovarian cancer cells, while suppressed the levels of pyruvate and lactate, the primary metabolites of glycolysis, ultimately leading to a reduction in cellular ATP content. Moreover, ALO suppressed the glycolytic protein expression of GLUT1, PKM2 and LDHA in ovarian cancer cells. MDM2, JAK2, and CDK2 were identified as the most promising targets of ALO in ovarian cancer.
CONCLUSION: ALO demonstrates anti-ovarian cancer effects both in vitro and in vivo through the enhancement of TCA cycle and reversing of aerobic glycolysis in ovarian cancer cells, providing a robust experimental foundation for future investigation of the potential clinical utility of ALO in ovarian cancer therapy.

Keywords: ALO; TCA; glycolysis; metabolomics; network pharmacology; ovarian cancer

DOI: https://doi.org/10.1016/j.jep.2026.121460

Ecotoxicol Environ Saf. 2026 Mar 03. pii: S0147-6513(26)00241-1. [Epub ahead of print]312 119912

Benzo[a]pyrene promotes gastric cancer progression via activation of the Correa cascade through modulation of the STAT3-TP53-MMP9 molecular axis.

Jiajia Tong, ShiYu Liu, Tingting Du, Wangting Liu, Ziyi Jin, Wenqing Si, Bingqian Zhang, Guangxia Chen.

To investigate the role of Benzo[a]pyrene (BaP) in driving the Correa cascade during gastric cancer development, we employed an integrated strategy combining network toxicology, machine learning, and molecular dynamics (MD) simulations. We identified 301 co-expressed genes spanning the Correa sequence, from chronic inflammation to invasive carcinoma. A protein-protein interaction network was constructed using STRING, and CytoHubba analysis highlighted five hub genes: TNF, IL6, IFNG, IL1B, and STAT3. Using CHEMBL and SUPER-PRED, we predicted 846 potential BaP targets. Intersection with disease-related genes revealed 62 common targets. Among eight candidate hub genes, an integrated Stepglm[both] and Random Forest model identified STAT3, TP53, and MMP9 as core targets. Receiver operating characteristic analysis confirmed their strong diagnostic potential (AUC > 0.78), while SHAP analysis ranked STAT3 as the most influential factor (SHAP = 0.241). Notably, these genes exhibited synergistic expression patterns in tumors (STAT3-TP53: ρ = 0.175; STAT3-MMP9: ρ = 0.261; TP53-MMP9: ρ = 0.216; all P < 0.01) and showed a dose-dependent association with disease progression. Genomic profiling revealed frequent mutations and amplifications in STAT3, TP53, and MMP9, with TP53 exhibiting the highest mutation rate. Analysis using UALCAN demonstrated significant upregulation of their mRNA levels in tumor tissues compared to normal tissues (P < 0.05). Clinically, high STAT3 and TP53 expression correlated with poorer survival, whereas elevated MMP9 levels were associated with improved outcomes. Mechanistic studies, including molecular docking and dynamics simulations, confirmed stable BaP-target interactions (e.g., STAT3 binding energy = -8.285 kcal/mol) mediated by non-covalent interactions, which disrupt the bidirectional STAT3-TP53 regulatory axis (STAT3 → MDM2 ⊣ TP53; TP53 → PIAS3 ⊣ STAT3). In summary, this study identifies STAT3, TP53, and MMP9 as central mediators of BaP-induced progression along the Correa cascade via a synergistic regulatory network. These findings provide new insights into environmental gastric carcinogenesis and highlight potential therapeutic strategies, including dual STAT3/MDM2 inhibition or MMP9 blockade.

Keywords: Benzo[a]pyrene; Correa cascade; Gastric cancer; Machine learning; Molecular dynamic simulation

DOI: https://doi.org/10.1016/j.ecoenv.2026.119912