Addition of PARP1-inhibition enhances chemoradiotherapy and thermoradiotherapy when treating cervical cancer in an <i>in vivo</i> mouse model

<b>Background:</b> Efficacy of current treatment options for cervical cancer require improvement. Previous <i>in vitro</i> 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 <i>in vitro</i> tumor models, <i>ex vivo</i> treated patient samples and <i>in vivo</i> tumor models. <b>Materials and Methods:</b><i>In vitro</i> clonogenic survival curves (0–6 Gy) show that PARP1<i>-i</i> (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 <i>in vivo</i> study, human cervical cancer (SiHa) cells were injected in the right hind leg of athymic nude mice. <i>In vivo</i> mouse experiments show that PARP1<i>-i</i> 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<i>-i</i> at 50 mg/kg. <b>Results:</b> Quadruple treatment, combining radiotherapy, hyperthermia, cisplatin and PARP1<i>-i</i>, 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-<i>i,</i> were effective without serious side effects. <b>Conclusion:</b> The triple combinations are promising options for potentially more effective treatment of locally advanced cervical cancer without more toxicity.