Tristan Montier

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

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.

Suicide gene strategies applied in ovarian cancer studies

Ovarian cancer represents the most lethal gynecological malignancy among women in developed countries. Despite the recent innovations, the improvements in the 5-year survival rate have been insufficient and the management of this disease still remains a challenge. The fact that the majority of patients experience recurrent or resistant disease have substantiated the necessity of an innovative treatment. Among various strategies investigated, the recent strides made in gene delivery techniques have made gene therapy, including suicide gene strategies, a potential alternative for treating ovarian cancer. Various suicide gene candidates, which are capable of promoting cancer cell apoptosis directly after its entry or indirectly by prodrug administration, can be separated into three systems using enzyme-coding, toxin or pro-apoptotic genes. With this review, we aim to provide an overview of different suicide genes depending on therapeutic strategies, the vectors used to deliver these transgenes specifically to malignant cells, and the combined treatments of these genes with various therapeutic regimens.