bims-midomi 2026-02-01 papers

World J Clin Oncol. 2026 Jan 24. 17(1): 111426

Evaluating murine double minute 2 status as a stratification tool for risk-adapted management in plasma cell neoplasms.

Noura A A Ebrahim, Habiba Elfandy, Aya Mohamed Adel Arafat, Amira Diyaa Darwish, Mahitab Ibrahim Eltohamy.

BACKGROUND: The E3 ubiquitin ligase murine double minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53 and has been implicated in the development of various cancers, including hematologic malignancies. In multiple myeloma (MM), increased MDM2 expression has been reported and may play a role in disease progression and resistance to therapy. Despite this, the prognostic implications of MDM2 detected through immunohistochemistry (IHC) remain insufficiently defined.
AIM: To evaluate the clinical, pathological, and prognostic significance of MDM2 expression in plasma cell neoplasms, with a focus on its potential utility as an early indicator of disease severity and therapeutic response.
METHODS: A retrospective analysis was conducted on 71 patients diagnosed with MM or related plasma cell disorders treated at the National Cancer Institute between 2018 and 2022. MDM2 protein expression was assessed using IHC on extramedullary lesion biopsy samples, employing the MDM2 (A.M.1) monoclonal antibody. Nuclear staining in at least 1% of plasma cells was used as the threshold for MDM2 positivity. Comparative analyses were performed between MDM2-positive and MDM2-negative groups, examining clinical characteristics, laboratory data, histopathological features, treatment responses at 12 weeks and 24 weeks, and survival outcomes, including relapse-free survival (RFS) and overall survival.
RESULTS: MDM2 expression was identified in 30% of patient samples. While no major differences were observed in baseline demographics, disease stage, or most laboratory values, serum albumin levels were significantly lower in MDM2-positive patients (P = 0.007). At 12 weeks, patients with MDM2-positive disease showed significantly poorer treatment responses based on International Myeloma Working Group criteria (P = 0.002), and early clinical response was moderately negatively correlated with MDM2 expression (Spearman's P = 0.375, P = 0.001). This correlation was not observed at 24 weeks. Immunophenotypic analysis indicated that MDM2-positive plasma cells exhibited lower epithelial membrane antigen (P = 0.014) and higher CD45 expression (P = 0.039), suggesting altered differentiation. Kaplan-Meier survival analysis demonstrated a markedly shorter median RFS in the MDM2-positive group (22 months vs 68 months, P < 0.001), although no significant difference was found in overall survival.
CONCLUSION: IHC-detected MDM2 overexpression identifies a distinct subset of plasma cell neoplasms characterized by reduced early treatment responsiveness and significantly shorter RFS. These findings support the potential of MDM2 as a prognostic biomarker for early relapse risk in MM. Incorporating MDM2 assessment into diagnostic and prognostic workflows may enable more individualized treatment approaches. Further validation through prospective studies is recommended.

Keywords: CD45; Epithelial membrane antigen; Immunohistochemistry; Multiple myeloma; Murine double minute 2; Plasma cell neoplasms; Prognostic biomarker; Relapse-free survival; Risk stratification; p53 pathway

DOI: https://doi.org/10.5306/wjco.v17.i1.111426

JCI Insight. 2026 Jan 27. pii: e197261. [Epub ahead of print]

AML PATIENTS WITH WILDTYPE TP53 BUT DEFECTIVE TP53-MEDIATED APOPTOSIS HAVE A DISMAL SURVIVAL.

Josephine Dubois, Anthony Palmer, Darren King, Mohamed Rizk, Karan Bedi, Kerby A Shedden, Sami N Malek.

The survival of patients with acute myelogenous leukemia (AML) carrying mutations in TP53 is dismal. We report the results of a detailed characterization of responses to treatment ex vivo with the MDM2 inhibitor MI219, a p53 protein stabilizer, in AML blasts from 165 patients focusing analyses on TP53 wildtype (WT) patients. In total 33% of AML were absolute resistant to MDM2 inhibitor induced apoptosis, of which 45% carried TP53 mutation and 55% were TP53 WT. We conducted array-based expression profiling of ten resistant and ten sensitive AML cases with WT TP53 status, respectively, at baseline and after 2h and 6h of MDM2 inhibitor treatment. While sensitive cases showed the induction of classical TP53 response genes, this was absent or attenuated in resistant cases. In addition, the sensitive and resistant AML samples at baseline profoundly differed in the expression of inflammation-related and mitochondrial genes. No TP53 mutated AML patient survived. The 4-year survival of AML with defective MDM2 inhibitor induced TP53-mediated apoptosis despite WT TP53 was dismal at 19% when NPM1 was co-mutated and 6% when NPM1 was WT. In summary, we identified prevalent multi-causal defects in TP53-mediated apoptosis in AML resulting in extremely poor patient survival.

Keywords: Apoptosis; Cell biology; Leukemias; Oncology; p53

DOI: https://doi.org/10.1172/jci.insight.197261

Pharmaceuticals (Basel). 2026 Jan 13. pii: 138. [Epub ahead of print]19(1):

Discontinued BACE1 Inhibitors in Phase II/III Clinical Trials and AM-6494 (Preclinical) Towards Alzheimer's Disease Therapy: Repurposing Through Network Pharmacology and Molecular Docking Approach.

Samuel Chima Ugbaja, Hezekiel Matambo Kumalo, Nceba Gqaleni.

Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors demonstrated amyloid-lowering efficacy but failed in phase II/III clinical trials due to adverse effects and limited disease-modifying outcomes. This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer's disease (AD). Methods: Drug-associated targets were intersected with AD-related genes to construct a protein-protein interaction (PPI) network, followed by topological analysis to identify hub proteins. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed using statistically significant thresholds (p < 0.05, FDR-adjusted). Molecular docking was conducted using AutoDock Vina to quantify binding affinities and interaction modes between the selected compounds and the identified hub proteins. Results: Network analysis identified 10 hub proteins (CASP3, STAT3, BCL2, AKT1, MTOR, BCL2L1, HSP90AA1, HSP90AB1, TNF, and MDM2). GO enrichment highlighted key biological processes, including the negative regulation of autophagy, regulation of apoptotic signalling, protein folding, and inflammatory responses. KEGG pathway analysis revealed significant enrichment in the PI3K-AKT-MTOR signalling, apoptosis, and TNF signalling pathways. Molecular docking demonstrated strong multitarget binding, with binding affinities ranging from approximately -6.6 to -11.4 kcal/mol across the hub proteins. Umibecestat exhibited the strongest binding toward AKT1 (-11.4 kcal/mol), HSP90AB1 (-9.5 kcal/mol), STAT3 (-8.9 kcal/mol), HSP90AA1 (-8.5 kcal/mol), and MTOR (-8.3 kcal/mol), while Lanabecestat showed high affinity for AKT1 (-10.6 kcal/mol), HSP90AA1 (-9.9 kcal/mol), BCL2L1 (-9.2 kcal/mol), and CASP3 (-8.5 kcal/mol), respectively. These interactions were stabilized by conserved hydrogen bonding, hydrophobic contacts, and π-alkyl interactions within key regulatory domains of the target proteins, supporting their multitarget engagement beyond BACE1 inhibition. Conclusions: This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand-hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer's disease, warranting further in silico refinement and experimental validation.

Keywords: Alzheimer’s disease; BACE1; drug repurposing; molecular docking; network pharmacology

DOI: https://doi.org/10.3390/ph19010138