PARP7 as a new therapeutic target in ovarian cancer

• Applicants: Professor Dr. Holger Bronger; Dr. Vanessa Küntzel
• Subject Area: Gynaecology and Obstetrics
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572705896

Ovarian cancer still has a poor prognosis with a 5-year survival rate of only about 50%. In contrast to other malignancies, immunotherapies such as immune checkpoint blockade against PD-1/PD-L1 have so far only shown disappointing results. One main reason seems to be insufficient immune infiltration or activation in ovarian cancer. The cGAS/STING pathway can improve both by inducing an interferon-like immune response and releasing T cell-recruiting and -activating cytokines and chemokines from tumor cells. PARP1/2 inhibitors such as olaparib or niraparib, both of which have had groundbreaking success in recent years, at least in some ovarian cancer patients, function in part by activating this STING signaling pathway. PARP7, another member of the poly-(ADP)-ribose polymerase family, is able to effectively inhibit the STING signaling pathway. Since PARP7 is much more strongly expressed in ovarian cancer than in other tumor types, it could be a reason for the general immunosuppression in this entity on the one hand, and for resistance to PARP1/2 or immune checkpoint inhibitors on the other. However, little is known about PARP7 in ovarian cancer. Our preliminary work shows that pharmacological PARP7 inhibition can massively and synergistically enhance the STING-dependent, tumor suppressive cytokine release from human and murine ovarian cancer cells, e.g. in concert with STING agonists or PARP1/2 inhibitors. In addition, PARP7 inhibition is also directly cytotoxic depending on PARP7 expression in the tumor cells. In this project proposal, we want to further elucidate the role of PARP7 in ovarian cancer: in the first subproject, the influence of PARP7 and its interactome on cytokine and chemokine release as well as on basic cellular properties of tumor cells will be further characterized. In the second subproject, the modulation of the intratumoral immune milieu and the influence of PARP7 on tumor growth and metastasis in syngeneic ovarian cancer mouse models will be investigated. The third subproject deals with the role of PARP7 in the development of resistance to PARP1/2 and immune checkpoint inhibitors or their combination, as tested in numerous current clinical trials. In the fourth subproject, the prognostic and predictive significance of PARP7 and associated proteins in human ovarian cancer will be investigated, also using patient cohorts from prospective clinical trials. The aim is to identify PARP7 as a new therapeutic target to improve the immune response, but also to prevent resistance, in ovarian cancer. In view of the fact that PARP7 inhibitors are already being tested in clinical phase I trials in other malignancies, this goal seems to us to be of utmost translational interest.

• DFG Programme: Research Grants