Introduction: Ovarian cancer (OC) is the eighth leading cause of cancer-related death among women worldwide, with over 300,000 new cases and 200,000 deaths annually. It is characterized by late diagnosis, molecular heterogeneity, and poor survival (~40% at 5 years). Inactivation of the tumour suppressor p53, mainly caused by TP53 mutations, occurs in more than 90% of high-grade serous carcinomas. Beyond loss of tumour-suppressive activity, mutant p53 (mutp53) frequently acquires oncogenic gain-of-function properties that promote tumour progression, immune evasion, and therapy resistance. Pharmacological reactivation of p53 therefore represents a promising therapeutic strategy. MANIO is a p53 activator capable of restoring wild-type-like activity to mutant p53. This study evaluated the anticancer potential of MANIO in OC.
Material and Methods: The anticancer effects of MANIO were evaluated as a single agent and combined with standard therapies using OC cell lines and patient-derived OC organoids. In vivo antitumor activity was assessed in xenograft mouse models harbouring mutant p53 by tumour volume measurements and immunohistochemical analyses. Statistical significance was determined using Student’s t-test or ANOVA (p < 0.05).
Results: MANIO showed selective antiproliferative activity in OC cells expressing wild-type or mutant p53, whereas p53-deficient cells were less sensitive. Cell-cycle analysis revealed G2/M arrest and increased sub-G1 population, consistent with apoptosis. In patient-derived OC organoids with different p53 statuses, MANIO induced dose-dependent growth inhibition, with IC50 values correlating with p53 status. MANIO also showed synergistic effects with oxaliplatin, paclitaxel, and olaparib. In vivo, it significantly inhibited tumour growth without evident toxicity. Immunohistochemical analyses revealed decreased proliferation, increased apoptosis, reduced angiogenesis, and downregulation of epithelial–mesenchymal transition markers.
Conclusion: MANIO demonstrates selective p53-dependent antitumor activity across OC models, including patient-derived organoids and xenografts, and enhances the efficacy of standard therapies. These findings support MANIO as a promising therapeutic strategy for ovarian cancer, particularly in tumours harbouring mutant p53.
Acknowledgements: This work received support from Portuguese national funds (FCT/MECI – Fundação para a Ciência e a Tecnologia and Ministério da Educação, Ciência e Inovação) through the project 2024.13556.PEX (https://doi.org/10.54499/2024.13556.PEX).
