bims-midomi 2025-12-14 papers

Med Oncol. 2025 Dec 12. 43(1): 54

A new approach for elimination of apoptotic resistance caused by MDM2/MDMX amplification in chronic lymphocytic leukemia: combination of ALRN-6924 and radiofrequency exposure.

Berrak Kurt, Handan Kayhan, Elçin Özgür Büyükatalay, Görkem Kısmalı.

Chronic lymphocytic leukemia (CLL) is characterized by mature B lymphocyte accumulation and frequent MDM2/MDMX overexpression, leading to p53 inactivation and apoptotic resistance. ALRN-6924, a stapled peptide dual inhibitor, targets MDM2/MDMX to restore p53 function. This study evaluated ALRN-6924 efficacy alone and combined with radiofrequency (RF) exposure in CLL cell lines. Molecular docking assessed ALRN-6924-MDM2 binding affinity. Cytotoxic and apoptotic effects were evaluated using XTT assays and flow cytometry in HG-3 (wild-type p53) and MEC-1 (mutant p53) cell lines. Treatments included ALRN-6924 monotherapy and combination with 900 MHz RF exposure (120 mW/cm2). MDM2, MDMX, BCL-2, and p53 protein levels were quantified by ELISA. Molecular docking revealed strong ALRN-6924-MDM2 binding (energy: - 9.30 kcal/mol, Ki: 163.9 nM). ALRN-6924 demonstrated potent cytotoxicity in HG-3 cells (IC50: 7.54 μM at 24 h, 5.88 μM at 48 h) versus resistance in MEC-1 cells (IC50: ~ 36 μM). In HG-3 cells, ALRN-6924 significantly induced apoptosis and necroptosis, reduced MDM2/MDMX expression, and enhanced p53 levels. RF combination therapy showed synergistic effects, further improving efficacy compared to monotherapy. BCL-2 expression was significantly reduced in the combination group. ALRN-6924 demonstrates promising therapeutic potential in wild-type p53 CLL cells, with enhanced efficacy when combined with RF exposure. The compound effectively disrupts the MDM2/MDMX-p53 axis, restoring p53 function and inducing programmed cell death. In mutant p53 cells, combination therapy may provide partial benefits. These findings support ALRN-6924 clinical development as targeted therapy for p53-functional CLL, particularly in combination strategies.

Keywords: ALRN-6924; Apoptosis; Chronic lymphocytic leukemia; MDM2; MDMX; Radiofrequency exposure; Targeted therapy; p53 tumor suppressor

DOI: https://doi.org/10.1007/s12032-025-03169-3

Methods. 2025 Dec 04. pii: S1046-2023(25)00245-2. [Epub ahead of print]246 107-115

MDM2/p53-based live-cell quantitative FRET imaging for apoptosis drug discovery.

Zhiyu Xiao, Lingmin Xie, Ziru Wu, Xinghong Cai, Zhengfei Zhuang, Tongsheng Chen.

Targeting the interaction between P53 and MDM2 to re-activate P53 to induce apoptosis is an important strategy for cancer treatment. In this study, based on the unique advantages of in situ visualization, dynamic imaging, and quantitative analysis of living cell FRET imaging, a method for screening apoptotic drugs targeting p53-MDM2 interaction was developed. A stable model of Nutlin-3-induced apoptosis was established in MCF-7 cells, which was verified by reducing mitochondrial membrane potential and increasing the proportion of nuclear chromatin condensation (from 9.16 % to 50.55 %). Biochemical methods such as WB analysis found that after activating P53, BAX expression was up-regulated through a Puma-independent pathway, which promoted BAX oligomerization. Live-cell quantitative FRET imaging found that the maximum donor center FRET efficiency (EDmax) of CFP-p53 and YFP-MDM2 decreased from 0.50 to 0.22 after Nutlin-3 treatment, and the co-localization coefficient decreased significantly from 83 % to 22 %, confirmed that Nutlin-3 directly disrupted the interaction between P53/MDM2, promoting P53 nuclear translocation and apoptosis. This indicated that Nutlin-3 was a direct inhibitor of the P53/MDM2 interaction. Apoptosis drug screening was performed in MCF-7 cells, and we found that the EDmax was 0.29 and 0.31 for the cells treated with DOX and RSV, respectively, and 0.48 for the IKE-treated cells and 0.43 for the SOR-treated cells, indicating that DOX and RSV, but not IKE and SOR, were potential P53/MDM2-dependent apoptotic drugs. In addition, Nutlin-3 treatment decreased the EDmax value in p53 wild-type U2OS cells from 0.43 to 0.20. In summary, our method can identify p53-MDM2 interaction inhibitors in living cells, providing a quantitative in vivo supplement for traditional target-based drug discovery.

Keywords: Drug discovery; FRET; MDM2; P53

DOI: https://doi.org/10.1016/j.ymeth.2025.12.002

Target Oncol. 2025 Dec 11.

Idasanutlin in Combination with Chemotherapy or Venetoclax in Pediatric and Young Adult Patients with Relapsed/Refractory Solid Tumors (iMATRIX Idasa): Results of a Phase I/II, Multicenter, Multi-arm Study.

Alba Rubio-San-Simón, Lynley V Marshall, Francois Doz, Jaume Mora, Kevin Bielamowicz, Nadege Corradini, Anne-Marie Langevin, Aru Narendran, Amy A Smith, C Michel Zwaan, Deborah Gho, Alison Cardenas, Stephen Fowler, Cecile Guizani, Vanessa Breton, Beate Wulff, Ronald Bernardi, Tanya Trippett, Quentin Campbell-Hewson.

BACKGROUND: MDM2 regulates the P53 pathway and is a promising therapeutic target, particularly in pediatric cancers with wild-type (WT) TP53. Idasanutlin is an investigational MDM2 inhibitor that is highly selective and orally bioavailable. The combination of MDM2 inhibition with cytotoxic chemotherapy or Bcl-2 inhibition has been shown to improve activity in preclinical models.
OBJECTIVE: iMATRIX idasa was designed to assess the safety, pharmacokinetics, and antitumor activity of idasanutlin in children and young adults with relapsed/refractory solid tumors.
PATIENTS AND METHODS: This multicenter phase I/II study enrolled patients aged < 30 years with extracranial solid tumors. Patients received idasanutlin on days 1-5 of a 28-day cycle as a single agent or in combination with venetoclax or chemotherapy. The single-agent dose escalation utilized a modified continual reassessment method. The primary endpoints included the safety and determination of the maximum tolerated dose, characterization of the pharmacokinetics, and preliminary efficacy.
RESULTS: Of 38 patients (median age 9 years [range: 2-23]), 26 with solid tumors received idasanutlin alone, and 12 with neuroblastoma received it in combination: six with venetoclax and six with chemotherapy (cyclophosphamide/topotecan). In total, 5 of 26 patients (19.2%) treated with single-agent idasanutlin experienced dose-limiting toxicities (including thrombocytopenia, neutropenia, and febrile neutropenia), which established a pediatric recommended phase II dose for idasanutlin of 4.5 mg/kg/day on days 1-5 of each 28-day cycle. The most frequently reported treatment-related adverse events were thrombocytopenia and neutropenia. Tolerable exposures were similar to what has been observed in adults. The objective response rate for patients with WT TP53 neuroblastoma who were treated with idasanutlin in combination with venetoclax or chemotherapy (primary efficacy endpoint) was 11.1% (N = 9; 95% confidence intervals, CI 0.28, 48.25) with one patient having a complete response. No other patients in the overall study population had an objective response.
CONCLUSIONS: The safety profile and tolerable exposure of idasanutlin in pediatrics was similar to that reported in adults. Limited clinical activity was observed in patients with solid tumors. On the basis of the negative benefit-risk assessment, the study was terminated, and the overall pediatric development program for idasanutlin was discontinued.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04029688, registered 19 July 2019.

DOI: https://doi.org/10.1007/s11523-025-01186-w