bims-midomi 2025-11-23 papers

Front Immunol. 2025 ;16 1684611

Selenium nanoparticle-delivered MDM2 inhibitor reactivates p53 and reprograms tumor immune microenvironment in colorectal cancer.

Weiming You, Jun Feng, Litao Guo, Jin Yan, Siqi Yan.

Background: Colorectal cancer (CRC) remains a major global health challenge, with limited immunotherapy efficacy in microsatellite stable (MSS) tumors that comprise ~85% of cases. The p53 tumor suppressor pathway, frequently inactivated through the mouse double minute 2 homolog (MDM2) overexpression in wild-type tumor protein 53(TP53) tumors, represents a promising therapeutic target for both direct antitumor effects and immune modulation.
Methods: We developed selenium nanoparticles loaded with the MDM2-targeting peptide inhibitor MI (Se@MI) using a one-pot synthesis approach. The nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, and UV-Vis spectroscopy. In vitro assays included MTT cytotoxicity evaluation, cellular uptake by flow cytometry, RNA-seq, and Western blotting of p53-pathway/apoptosis markers. Antitumor efficacy was evaluated in CT26 murine colorectal cancer models, with mechanistic studies including transcriptomic analysis, immunohistochemistry, and flow cytometry. Safety profiles were assessed through body weight monitoring, hematological analysis, histopathological examination of major organs, and serum biomarker evaluation.
Results: Se@MI nanoparticles demonstrated uniform spherical morphology (45-50nm diameter) and displayed a positive zeta potential (+24.69 mV), indicative of favorable colloidal dispersibility. Enhanced cellular uptake (74.3% positive cells) and potent cytotoxicity (IC50 = 1.00 μM) were observed in CT26 cells. Transcriptomic analysis revealed significant activation of p53 signaling pathways (NES = 1.504, P = 0.029) and protein analyses confirmed induction of p21, PUMA, Bax, and cleaved caspase-3. In vivo, Se@MI treatment achieved 72.23% tumor growth inhibition, significantly outperforming controls. Mechanistically, Se@MI restored p53 function by disrupting MDM2-p53 interactions, inducing apoptosis and cell cycle arrest. Importantly, Se@MI reprogrammed the tumor immune milieu through increased infiltration of CD8+ T cell and cytotoxic function while suppressing regulatory T cells. Comprehensive safety evaluation revealed excellent biocompatibility with no adverse effects on body weight, hematological parameters, organ histology, inflammatory cytokines, or hepatic/renal function markers.
Conclusions: Se@MI represents a novel nanomedicine strategy that combines direct p53 pathway reactivation with immune microenvironment modulation. This dual mechanism of action offers a potential strategy to boost immunotherapeutic outcomes in colorectal carcinoma and may help overcome resistance mechanisms to immune checkpoint blockade.

Keywords: antitumor; p53 reactivation; peptide; selenium nanoparticles; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2025.1684611

Sci Rep. 2025 Nov 18. 15(1): 40363

Antineoplastic 4-piperidone-1-phosphonothioates with potential multi-targeted inhibitory properties.

Mohamed S Bekheit, Siva S Panda, Benson M Kariuki, Walid Fayad, Ahmed A F Soliman, Hanaa Farag, Adel S Girgis.

A set of 3,5-bis(ylidene)-4-piperidone-1-phosphonothioates 20a‒l was synthesized in high yields through dehydrochlorination reaction of 3,5-bis(ylidene)-4-piperidones 18a‒l and diethyl chlorothiophosphate 19 in DMF containing quantitative amounts of TEA at 0 °C. Most of the synthesized agents exhibit effective antiproliferation properties against a variety of cancer cell lines (MCF7/breast, HCT116/colon, and A431/skin), outperforming the efficacy of the clinically approved drugs. Compound 20c (R = 3-ClC6H4) is the most effective analog discovered with a sub-micromolar activity against MCF7 (IC50 = 0.650, 3.15 and 3.97 µM, for 20c, 5-fluorouracil, and sunitinib, respectively) as well as remarkable efficacy against HCT116, and A431 (IC50 = 1.445 and 2.920 µM respectively for 20c, compared to 20.43 and 23.44 µM respectively for 5-fluorouracil). The synthesized analogs demonstrating considerable anti-MCF7 properties were evaluated for their biochemical properties against MDM2, p53, and topoisomerase I/II. Compound 20k [R = 3,4,5-(MeO)3C6H2] is the most effective anti-MDM2 agent with a potency higher than the standard reference (% inhibition of 65.3, for 20k, and 42.2 for doxorubicin; i.e. 1.55-fold). Biochemical activation of p53 by the synthesized analogs is consistent with the anti-MDM2 properties. Compound 20i (R = 4-MeOC6H4) is the most effective topo-I and topo-IIα inhibitor with potency close to that of the standard references (Dxd, and etoposide). Some of the synthesized agents showed selectivity for topo-IIα over topo-I. Molecular docking results (PDB: 4OAS) are consistent with the observed properties against MDM2. Based on the biological and biochemical findings, some of the synthesized compounds could serve as promising multi-targeted inhibitors.

Keywords: 4-Piperidone-1-phosphonothioate; Cancer; MDM2-p53; Molecular modeling; Topoisomerase

DOI: https://doi.org/10.1038/s41598-025-25796-6

Virchows Arch. 2025 Nov 21.

Criteria for MDM2 fluorescence in situ hybridization testing in the diagnosis of well-differentiated adipocytic neoplasms: a retrospective utilization review of 1151 cases.

Ashley N Flaman, Lingxin Zhang, Brendan C Dickson, Elizabeth G Demicco.

Demonstration of MDM2 amplification is currently recommended to confirm the diagnosis of well-differentiated adipocytic tumors arising in the retroperitoneum, abdomen, and pelvis; recurrent "lipomas"; those with equivocal cytologic atypia; deep extremity tumors >10 cm which lack cytologic atypia and occur in patients >50 years old, and in special clinical circumstances (Clay et al., 2015 [Clay criteria]). In our practice, fluorescence in situ hybridization studies (FISH) for MDM2 were historically performed for all referred-in testing requests, for all well-differentiated fatty tumors >10 cm, and to confirm the diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) in cases with definite atypia. As part of a test utilization review, after exclusion of dedifferentiated liposarcoma, we reviewed 1151 ostensibly fatty tumors on which FISH was successfully performed. After exclusion of 203 cases for which testing was inappropriate or indicated for other reasons, 233/948 (24.6%) fatty tumors met at least one Clay criterion, and 222 (23.4%) had definite nuclear atypia. Among tumors with definite atypia, 152 (68.5%) were ALT/WDL, and 48 (21.6%) were spindle cell/pleomorphic lipoma arising in unusual locations or atypical spindle cell/pleomorphic lipomatous tumors. Thirty (12.9%) cases meeting any Clay criteria were ALT/WDL, and 4/453 (0.9%) tumors not meeting Clay criteria or having atypia were ALT/WDL. The sensitivity of Clay criteria plus nuclear atypia for ALT/WDL was 97.8%, while specificity was 62.7%. We conclude that it is safe to defer MDM2 FISH in well-differentiated fatty tumors not meeting Clay criteria and lacking nuclear atypia.

Keywords: Atypical lipomatous tumor; Atypical spindle cell/pleomorphic lipomatous tumor; MDM2; Testing criteria; Well-differentiated liposarcoma

DOI: https://doi.org/10.1007/s00428-025-04342-9

Clin Transl Oncol. 2025 Nov 17.

Sex-based molecular and prognostic disparities in pan-cancer: an analysis across the global cohorts.

Guruguhan Sivakumar, Tapas Patra, Durgadevi Veeraiyan, Akhileshwar Namani.

BACKGROUND: Biological sex influences cancer risk, molecular profiles, and clinical outcomes, yet its role in non-reproductive cancers remains underexplored.
METHODS: This study investigated sex-based differences in somatic mutations, copy number alterations (CNAs), and overall survival (OS) across 34,782 patients from three global pan-cancer cohorts (TCGA, MSK MetTropism, and China OrigiMed), excluding reproductive cancers to minimize confounders. Sex-specific genetic alterations were assessed using Fisher's exact test, while OS differences were evaluated with Kaplan-Meier and Cox proportional hazards models.
RESULTS: Incidence patterns revealed a strong male predominance in esophageal, liver, bladder, and head and neck cancers, whereas thyroid and gallbladder cancers were more common in females. OS analysis showed a consistent female advantage in both primary and metastatic cohorts, with males experiencing poorer OS in lung adenocarcinoma, glioblastoma, and pancreatic adenocarcinoma, although colorectal cancer with hepatic metastases favored males. Mutational profiling revealed that the TP53, CDKN2A, and TTN mutations were more frequent in males, while EGFR, KRAS, BRAF, and PIK3CA mutations occurred more often in females. Notably, BRAF and EGFR mutations were associated with better survival in females. CNAs analysis demonstrated male-biased amplifications, including CCND1 and the FGF cluster in the China cohort, and MYC, CCND1, and ERBB2 in the TCGA and MSK cohorts. In contrast, MDM2 amplification was enriched in females in the China cohort.
CONCLUSION: These findings highlight both shared and population-specific molecular differences and underscore the importance of integrating sex as a biological variable in cancer genomics, biomarker development, and clinical trial design.

Keywords: Cancer; Mutations; Pan-cancer; Prognosis; Sex; Survival

DOI: https://doi.org/10.1007/s12094-025-04104-8