2. Academic Validation
  3. Modified hTERT promoters-driven purine nucleoside phosphorylase-gene therapy in association with chemo- and targeted therapy in the context of ovarian cancer

Modified hTERT promoters-driven purine nucleoside phosphorylase-gene therapy in association with chemo- and targeted therapy in the context of ovarian cancer

  • Cancer Gene Ther. 2025 Aug;32(8):843-853. doi: 10.1038/s41417-025-00932-6.
Quoc Manh Nguyen 1,  Pierre-François Dupré 1 2,  Mathieu Berchel 3,  Marylène Lévêque 4,  Sylvie Choblet-Thery 4,  Frédérique d'Arbonneau 1 5,  Tristan Montier 6 7 8
Affiliations

Affiliations

  • 1 Univ Brest, Inserm, EFS, UMR 1078, GGB, GTCA team, "Gene Transfer and Combined therapeutic Approaches", Brest, France.
  • 2 CHU de Brest, Service de Chirurgie Gynécologique, Brest, France.
  • 3 Univ Brest, CNRS, CEMCA UMR 6521, 6 Avenue Victor Le Gorgeu, Brest, France.
  • 4 CNRS UAR3426, BACFLY "Baculovirus et Thérapie", Saint-Christol-Lez-Alès, France.
  • 5 CHU de Brest, Service d'Odontologie, UFR d'Odontologie de Brest, Brest, France.
  • 6 Univ Brest, Inserm, EFS, UMR 1078, GGB, GTCA team, "Gene Transfer and Combined therapeutic Approaches", Brest, France. tristan.montier@univ-brest.fr.
  • 7 CHU de Brest, Service de Génétique Médicale et de Biologie de la Reproduction, Brest, France. tristan.montier@univ-brest.fr.
  • 8 CHU de Brest, Centre de Référence des Maladies Rares "Maladies Neuromusculaires", Brest, France. tristan.montier@univ-brest.fr.
PMID: 40579465 DOI: 10.1038/s41417-025-00932-6
Abstract

Ovarian Cancer has the highest mortality-to-incidence ratio among gynecologic cancers worldwide. E.coli Purine Nucleoside Phosphorylase-based gene-directed enzyme prodrug therapy (PNP-GDEPT) offers a promising alternative for the treatment of solid tumors. This study proposes an original ovarian Cancer treatment through the use of two recently developed modified hTERT promoters: the mutated hTERT (hTERTm) and the chimeric hTERT-CMV. Four plasmids were engineered to investigate the effects of cancer-specific PNP gene expression: pCMV-PNP, phTERT-PNP, phTERTm-PNP, and phTERT-CMV-PNP. The cationic lipid formulation BSV163/DOPE was employed to transfect PNP-coding plasmids into cisplatin-sensitive ovarian Cancer cells and their resistant counterparts. hTERT-driven PNP-GDEPT selectively reduced Cancer cell viability while sparing primary human fibroblasts. In addition, combining PNP-GDEPT with either cisplatin or olaparib further enhanced Anticancer effects on cell viability and Apoptosis. However, no combined effects were observed for the concurrent use of cisplatin and olaparib, with or without PNP-GDEPT. Our results demonstrate that targeted PNP-GDEPT has the potential to enhance the efficacy of chemotherapy and targeted therapy against ovarian Cancer while minimizing side effects on healthy cells. This treatment is effective irrespective of cisplatin resistance status and warrants further investigation.

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