Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms

Abstract

It has long been established that hyperthermia increases the therapeutic benefit of radiation and chemotherapy in cancer treatment. During the last few years there have been substantial technical improvements in the sources used to apply and measure heat, which greatly increases enthusiasm for the clinical use of hyperthermia. These advances are converging with a better understanding of the physiological and molecular effects of hyperthermia. Therefore, we are now at a juncture where the parameters that will influence the efficacy of hyperthermia in cancer treatment can be optimised in a more systematic and rational manner. In addition, the novel insights in hyperthermia's many biological effects on tumour cells will ultimately result in new treatment regimes. For example, the molecular effects of hyperthermia on the essential cellular process of DNA repair suggest novel combination therapies, with DNA damage response targeting drugs that should now be clinically explored. Here, we provide an overview of recent studies on the various macroscopic and microscopic biological effects of hyperthermia. We indicate the significance of these effects on current treatments and suggest how they will help design novel future treatments. ARTICLE HISTORY

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

“…While radiosensitisation by increased perfusion and reoxygenation [43,44] can be observed already at 39 C, the effect increases substantially with increasing temperature with more direct radiosensitisation due to the inhibition of DNA damage repair machinery [45][46][47]. Also chemosensitisation starts at relatively low temperatures for many chemotherapy compounds, including drugs frequently used in pancreatic cancer, such as gemcitabine and fluorouracil [48][49][50][51].…”

Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies

“…The most wellinvestigated and well-known physiological effects of hyperthermia are the increase in local blood flow and the alterations in vascular permeability, and the change in tumour microenvironment [14,15]. Another physiological effect of hyperthermia that has recently gained more attention is the activation of the immune response by heat [16,17].…”

“…Hyperthermia sensitises tumour cells to radiation and chemotherapy by altering tumour biology, both at the physiological and molecular level [13,14]. The most wellinvestigated and well-known physiological effects of hyperthermia are the increase in local blood flow and the alterations in vascular permeability, and the change in tumour microenvironment [14,15].…”

Homologous recombination preferentially repairs heat-induced DNA double-strand breaks in mammalian cells

“…Several lines of evidence show that factors involved in DSB repair are likely to be affected by heat shock, for example, Ku heterodimer (Ku70/Ku80) [33][34][35][36], MRN complex [37][38][39], breast cancer susceptibility gene 1 (BRCA1) [40], BRCA2 [41] and RAD51 [41,42]. Heat shock affects these proteins by causing denaturation, cytoplasmic translocation from the nucleus, and protein degradation by the proteasome pathway [43]. These biological observations are currently proposed as possible reasons why IR combined with heat shock results in increased cell death with excessive unrepaired DSBs compared with IR alone [44].…”