Multimodal oncological strategies which combine chemotherapy or radiotherapy with hyperthermia (i.e. raising the temperature of a region of the body affected by cancer) 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. However , HSR triggers thermotolerance, i.e. the hyperthermia treated cells show an impairment in their susceptibility to a subsequent heat-induced stress. For that reason, the application of the combined hyperthermia therapy should be carefully examined . We adapt our previous HSR model and propose its stochastic extension, which we then analyze using the approximate probabilistic model checking (APMC) technique. We formalize the notion of the thermotolerance and compute the size and the duration of the HSR-induced thermotolerance. We quantify the effect of a combined therapy of hyperthermia and a cytotoxic inhibition of proteins refolding . By mechanistic modeling 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 signaling 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 (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 thermotolerance and 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.
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heat shock
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For that reason, the application of the combined hyperthermia therapy should be carefully examined
This poses a question about the efficacy and about an optimal strategy of the therapy combined with hyperthermia treatment
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analyze
analyse
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formalize
formalise
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compute the size
estimate the intensity
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multimodal therapy based on
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inhibition of proteins refolding
effect of bortezomib, a proteasome inhibitor, and we propose an optimal strategy for combining these two modalities
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modeling
modelling
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signaling
signalling