Tumor cells can’t stand the heat: Boosting the effectiveness of hyperthermia in cervical carcinoma

Mild hyperthermia, e.g. local heating of the tumor to 40-42.5°C for approximately one hour, is a clinically applied anti-cancer treatment to sensitize radiotherapy and/or chemotherapy. Hyperthermia has already been applied since the 1980s, with convincing evidence in in vitro and in vivo models and in many clinical trials. However, only the tip of the iceberg is known of how hyperthermia enhances the effects of radiotherapy and chemotherapy. In Part I of this thesis, we investigated the mechanisms of response to hyperthermia. In particular, we provide a new mechanism on how hyperthermia affects HPV-positive cervical carcinoma. Part II of this dissertation is allocated to investigate the sequences of and the time interval between applying hyperthermia and radiotherapy, as there is no worldwide consensus about these matters. The best protocol aims at the highest induction of DNA damage in cancer cells, with tolerable, and preferably as minimal as possible, side-effects. Part III considers novel multimodalities with hyperthermia, to increase treatments effectiveness. Remarkably, addition of PARP1-inhibitors to hyperthermia and cisplatin, allows a ten-fold reduction of cisplatin dose, without decreasing tumor cell death. The work discussed in this thesis did lead to more insight in the working mechanisms of hyperthermia, thus to optimization of the application of hyperthermia in the clinic and to novel promising multimodality treatments. The overall conclusion therefore is that, as tumor cells can’t stand the heat, the effectiveness of cervical cancer treatment can be boosted by hyperthermia