Hyperthermia-induced degradation of BRCA2 : from bedside to bench and back again

Abstract

Local hyperthermia, a method during which the temperature of a tumor is elevated, clinically increases the efficacy of radiotherapy and chemotherapy, without increasing side-effects. One of the reasons that explains why hyperthermia increases effectivity of these therapies is that it induces degradation of BRCA2. BRCA2 is an essential protein for double strand break DNA repair via homologous recombination (HR). Double strand breaks are the types of damage that occur after radiotherapy and specific types of chemotherapy, and are the basis for the anti-cancer effects of these therapies. By inhibiting HR, hyperthermia prevents repair of these breaks, and therefore increases anti-cancer efficacy of radiotherapy and chemotherapy. This thesis describes the journey of hyperthermia-mediated BRCA2 degradation, from bedside to bench and back again. In the __Prequel__ we describe bedside to bench research that has provided biological explanation for why hyperthermia sensitizes to radiotherapy through hyperthermia-mediated degradation of BRCA2. By taking __a Step Back__ we identify the thermal doses and the hyperthermia-radiotherapy sequencing necessary to best exploit heat-mediated BRCA2 degradation in the clinical setting. Next, with a Bench to Bedside approach, we explore what hyperthermia-mediated BRCA2 degradation and the resulting HR-deficiency can currently contribute to clinical hyperthermia treatment. Lastly, we close the __Bedside to Bench__-circle by addressing how clinical hyperthermia can be improved by exploring new targets for increasing effectiveness of hyperthermia-mediated BRCA2 degradation, using laboratory experiments