From senescence to cell death: anti-SASP treatment and senolytics against SCAP

• Applicant: Professorin Maja Tomicic-Christmann, Ph.D.
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508828494

Malignant glioma, especially glioblastoma, is one of the worst performing tumor types with no chance of survival for the person affected. The already moderate success of temozolomide (TMZ) - based therapy depends on an effective triggering of cell death. In addition to cell death, however, there is also the induction of senescence in tumor cells. This occurs in the G2/M phase of the cell cycle, triggered by the ATR/CHK1-mediated degradation of CDC25c and the induction of p21. Furthermore, we were able to show that senescence is dependent on activation of the NF-κB signaling pathway and is associated with activation of proteins of the inhibitor of apoptosis family (IAPs). Therefore, these factors presumably play an important role in specific senescent-cell anti-apoptotic pathways (SCAP). An important mechanism triggered by senescence is the senescence-associated secretory phenotype (SASP), characterized by the formation of multiple immune factors. In preliminary experiments, we were able to show that TMZ triggers the SASP in glioblastoma cells in addition to senescence. We are planning to investigate specific SASP and SCAP factors in primary and recurrent glioblastoma patients' samples. The meaning of the SASP is contradictory. On one hand, it can enhance senescence, but on the other, it can increase the proliferation of neoplastic epithelial cells, promote epithelium-to-mesenchyme transition (EMT), and increase tumor growth in vivo. The study aims to examine the role of SASP, NF-κB signaling pathway and the importance of IAPs for senescence and resistance to TMZ in vitro and ex vivo. In particular, we plan to investigate the molecular mechanisms leading to SASP after TMZ treatment. Furthermore, we want to analyze the influence of SASP on the maintenance of TMZ-induced senescence, EMT and invasion. With regard to the IAPs, we want to investigate whether they are responsible for the maintenance of senescence within the SCAP and whether inhibitors of the IAPs are suitable senolytics. Besides testing compounds targeting SCAP and SASP, we will also screen for compounds with an established senotherapeutic (senolytic and senomorphic) activity as to their efficiency towards senescent glioblastoma cells. In addition, using patient-derived glioblastoma-initiating cells forming neurospheres it will be examined whether TMZ triggers senescence and SASP ex vivo, and whether senolytic and senomorphic drugs can improve the glioblastoma response to TMZ. The administration of TMZ in combination with the in vitro proven senolytics (BV6, venetoclax) will also be verified in a subcutaneous glioblastoma xenograft model in mice.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Markus Christmann