Project Details
Projekt
Therapeutic Induction and Image Guided Exploitation of Cellular senescence for Cancer Therapy
Applicants
Professor Dr. Bernd Pichler; Professor Dr. Lars Zender
Subject Area
Hematology, Oncology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939
Data acquired in the previous funding period led to the discovery of a novel type of cellular senescence, designated ribosomal checkpoint induced senescence (RCIS). Functional genetic screens identified components of the multiprotein complex of RNA Polymerase I dependent transcription as druggable targets to induce RCIS. Proof-of-concept studies in vitro and in vivo showed that CX-5461, a small molecule disrupting RNA Polymerase I dependent transcription, robustly induced therapy induced senescence (TIS). The parallel development of a novel first in class PET tracer, to detect senescence in living organisms, brings us now in the unique position to explore the concept of an image guided use of CX-5461 and other pro-senescence therapies.Studies in the context of Oncogene Induced Senescence (OIS) have shown that a sustained presence of senescent cells might promote cancer progression, however it is currently unclear whether TIS also exerts protumorigenic effects on adjacent non-senescent cancer cells. We will therefore set out to address this fundamental question in senescence biology using mouse models allowing to genetically induce TIS in a subfraction of cancer cells. As these cancer cells will be genetically engineered to express murine HB-EGF, a systemic application of Diptheria Toxin will allow for an efficient and site directed elimination of these cells. These studies will mimick the use of pharmacological senolytic therapies which are currently under development. The outlined system will allow us to probe the impact of therapy induced senescence (TIS) and senolytic strategies on liver cancer maintenance and progression. We furthermore will pursue strategies for a dual ribosome targeting for the treatment of colorectal cancer and other solid tumors. This aim can be seen as a bedside to bench approach, as we recently observed a pronounced therapy response towards CX-5461 in a patient with advanced therapy resistant colorectal cancer (CRC) carrying a heterozygous mutation of the Shwachman-Bodian-Diamond syndrome (SBDS) protein. We hypothesize that the patient showed a pronounced response because even a heterozygous loss of SBDS function might be associated with a defect in ribosome maturation and ribosomal stress and might thus be synthetic lethal with CX-5461 mediated inhibition of RNA Polymerase-I. Within this research project we will mechanistically characterize this possibility using in vitro and in vivo models. Finally, in close collaboration with Antti Poso (Z02), we aim to develop pharmacological tools and probes for direct or indirect inhibition of SBDS function.
DFG Programme
Research Units
