Inhibition of HSP90, combined with the suppression of HSF1 activity, for improved treatment of gastrointestinal cancers

• Applicant: Privatdozentin Dr. Ramona Schulz-Heddergott, Ph.D.
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531061262

The stress-associated chaperone system is an actionable target in cancer therapies. It stabilizes hundreds of oncoproteins, enabling tumorigenic lifestyle. Most inhibitors target the key component heat-shock protein 90 (HSP90). Although HSP90 inhibitors are highly tumor-selective, they also have pitfalls. The main problem is the activation of the heat-shock response (HSR) upon Hsp90 inhibition which diminishes their own efficiency. Because of our new findings we suggest to simultaneously inhibit the HSR by p53 activation under HSP90 inhibition. We found that wildtype p53 actively represses heat-shock factor 1 (HSF1) activity, the main inducer of the HSR via a p21-CDK4/6-E2F-MAPK axis. Thus, we will investigate whether a p53 activation or inhibition of cyclin dependent kinases (CDKs) diminish HSF1 and HSR activity in HSP90-based therapies. This will bring two advantages together, I) improving the efficiency of an HSP90 inhibition and II) to activate the tumor-suppressive p53 transcriptional program, or in case of CDK inhibition to additionally interfere with the cell cycle.

• DFG Programme: Research Grants