Design of hyperthermia protocols for inducing cardiac protection and tumor destruction by controlling heat shock protein expression
Heat shock proteins (HSP) are critical components of a complex defense mechanism essential for preserving cell survival under adverse environmental conditions. The presence of sub-lethal stressful stimuli, such as hyperthermia can induce HSP expression, thereby protecting cells from otherwise lethal insults. Thermally induced HSP expression in the heart can provide cardiac protection against ischemia reperfusion injury associated with cardiac surgery. However, thermally induced HSP expression during hyperthermia prostate cancer therapies can enhance tumor cell viability and resistance to subsequent chemotherapy and radiation treatments. Characterization of the thermally induced HSP kinetics is crucial for designing hyperthermia therapies that produce the desired HSP expression pattern most appropriate for the intended therapy outcome. This research focused on characterization of the thermally induced HSP kinetics in both cardiac cells and prostate cells and tissues to permit dosimetry guideline development and optimization models for controlling HSP expression induced during laser therapy. Although the initial design of thermal preconditioning protocols for inducing cardiac protection were explored, the majority of the dissertation will focus on cellular and tissue analysis methods and computational modeling strategies utilized in the development of a novel therapy planning tool for prostate cancer laser therapy. This work has focused on characterizing the thermally induced HSP27 and 70 expression kinetics for the prostate at the cellular and tissue level. Through the use of Magnetic Resonance Temperature Imaging which provided the spatiotemporal temperature distribution data and confocal microscopy, the HSP27 and 70 distributions were accurately determined throughout laser irradiated prostate tumors. The measured HSP expression data was employed to create the first HSP predictive computational model. A highly accurate, adaptive, finite element model was developed which is capable of predicting and optimizing the temperature, HSP expression, and damage distributions associated with laser heating in prostate tissue and tumors. Application of the treatment planning model in the design of prostate cancer thermal therapies can enable optimization of the treatment outcome by controlling the tissue response to therapy based on accurate prediction of the HSP expression and damage distributions.