Chapter V: Optimizing HT-based treatments by manipulating the heat shock…
Chapter V: Optimizing HT-based treatments by manipulating the heat shock response.
The heat shock response is abused by cancer cells to sustain stress caused by environment or genetic instability.
As overexpression of heat shock proteins correlates to the degree of stress tolerance, cancer cells overexpressing the heat shock response are intrisically more thermotolerant
Heat shock response partially governs most drawbacks experienced in current HT-based treatments
Targeting the heat shock response will interfere with the ability to generate or maintain a thermotolerant state
Limited therapeutic window
Targeting the heat shock response will hamper the ability of cells to reverse damage caused by HT, and could possibly extend the therapeutic window.
Insufficient target temperature
Targeting the heat shock response reders cells more sensitive to relatively lower temperature
The ability to generate a response to hyperthermia is a prerequisite to survive hyperthermia. Irrespective of the buildup of a tumour and the characterisitcs of cancer cells, these cells will have to respond to heat stress when provided.
Effectively targeting the heat shock response could potentially extend the range of tumour types that can be treated. (evidence : Mu et al 2018;
HT is currently combined with RT/CT to sensitize cancer cells to DNA-damaging treatments. However, there are many more effects of HT that we can utilize to improve such treatments. One overlooked component is the heat shock response.
Targeting the heat shock response further promotes the development of HT- based treatments into multi-modal therapies
Limitations to inhibit the heat shock response
Limited information on heat shock response in cancer cells
Most of our knowledge on the effects of heat shock are based on studies that focused on other organisms (check Richter).
Also, such studies often did not perform HT in the way we use it now in the clinic, namely 42C for 1h. We cannot simply extrapolate such findings to cancer cells.
Lack of inhibitors of heat shock response
Ways to inhibit heat shock response
Level of execution
HSP90 only FDA-approved drug.
Levels of sensing
HSF1: effort is made, but no approved and potent inhibitor yet.