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), which main component (the heat-shock proteins ) is known to directly prevent the intended apoptosis of cancer cells. Moreover, cancer cells can have an 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. the hyperthermia treated cells show an impairment in their susceptibility to a subsequent heat-induced stress. This poses a question about the efficacy and about an optimal strategy of the  therapy combined with hyperthermia treatment. We adapt our previous HSR model and propose its stochastic extension , which we then analyse using the approximate probabilistic model checking (APMC) technique . We formalise the notion of the thermotoleranceand estimate the intensity and the duration of the HSR-induced thermotolerance. Finally, we quantify the effect of a multimodal therapy based on hyperthermia and a cytotoxic effect of bortezomib, a proteasome inhibitor, and we propose an optimal strategy for combining these two modalities. By mechanistic modelling of HSR we are able to support the common belief that the combination of cancer treatment strategies increases therapy efficacy . Moreover, our results demonstrate feasibility and practical potential of APMC in analysis of stochastic models of signalling pathways .
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), which main component 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 .
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