Addition of PARP1-inhibition enhances chemoradiotherapy and thermoradiotherapy when treating cervical cancer in an mouse model.

Efficacy of current treatment options for cervical cancer require improvement. Previous studies have shown the enhancing effects of the addition of PARP1-inhibitors to chemoradiotherapy and thermoradiotherapy. The aim of our present study was to test efficacy of different combinations of treatment modalities radiotherapy, cisplatin, hyperthermia and PARP1-inhibitors using tumor models, treated patient samples and tumor models. clonogenic survival curves (0-6 Gy) show that PARP1 (4-5 M Olaparib) enhances both chemoradiotherapy (0.3-0.5 µM cisplatin) and thermoradiotherapy (42 °C for 1 h) in SiHa, CaSki and HeLa cells. A cervical cancer mouse model and freshly obtained in-house developed patient-derived organoids were used to examine the effects of different treatment combinations. For the study, human cervical cancer (SiHa) cells were injected in the right hind leg of athymic nude mice. mouse experiments show that PARP1 enhances thermoradiotherapy or chemoradiotherapy by reduction of tumor volumes. Five cycles of treatment were applied with the following doses per cycle: irradiation 3 Gy, hyperthermia 1 h at 42 °C, cisplatin at 2 mg/kg, and twice PARP1 at 50 mg/kg. Quadruple treatment, combining radiotherapy, hyperthermia, cisplatin and PARP1, was very effective but also lead to severe side effects causing severe weight loss and death. In contrast, thermoradiotherapy or chemoradiotherapy with addition of PARP1- were effective without serious side effects. The triple combinations are promising options for potentially more effective treatment of locally advanced cervical cancer without more toxicity.