Modelling the efficacy of hyperthermia treatment

TL;DR

This paper develops a stochastic model of the heat-shock response to evaluate hyperthermia-based cancer therapies, proposing optimal combination strategies with proteasome inhibitors to improve treatment efficacy.

Contribution

It introduces a stochastic extension of the HSR model, formalizes thermotolerance, and quantifies optimal hyperthermia and drug combination strategies.

Findings

Hyperthermia activates heat-shock proteins more in cancer cells.

Thermotolerance impairs susceptibility to subsequent heat stress.

Combining hyperthermia with proteasome inhibitors enhances therapy efficacy.

Abstract

Multimodal oncological strategies which combine chemotherapy or radiotherapy with hyperthermia have a potential of improving the efficacy of the non-surgical methods of cancer treatment. Hyperthermia engages the heat-shock response mechanism (HSR), main component of which are heat-shock proteins (HSP). Cancer cells have already partially activated HSR, thereby, hyperthermia may be more toxic to them relative to normal cells. On the other hand, HSR triggers thermotolerance, i.e. hyperthermia treated cells show an impairment in their susceptibility to a subsequent heat-induced stress. This poses questions about efficacy and optimal strategy of the anti-cancer therapy combined with hyperthermia treatment. To address these questions, we adapt our previous HSR model and propose its stochastic extension. We formalise the notion of a HSP-induced thermotolerance. Next, we estimate the intensity and the duration of the thermotolerance. Finally, we quantify the effect of a multimodal therapy based on hyperthermia and a cytotoxic effect of bortezomib, a clinically approved proteasome inhibitor. Consequently, we propose an optimal strategy for combining hyperthermia and proteasome inhibition modalities. In summary, by a proof of concept mathematical analysis of HSR we are able to support the common belief that the combination of cancer treatment strategies increases therapy efficacy. thermotolerance.