Seed Funding Programm 2022
RASCAL
Analysis of MAPK/RAS signaling and combined pathway inhibition to enhance radiation sensitivity in rectal cancer
Coordinators
Tianzuo Zhan
II. Medical Clinic/ Translational Gastrointestinal Oncology, UMM
dkfz.de
Johannes Betge
DKFZ-Hector Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, DKFZ
Detailed description
Rectal cancer is most frequently diagnosed in a locally advanced stage and usually treated by a combination of radiation, chemotherapy, and surgical resection. A complete response after neoadjuvant chemoradiation is associated with improved clinical outcome and may even allow omission of subsequent surgery. Current efforts therefore aim to increase complete response rates with intensified neoadjuvant concepts but are mainly focusing on toxic chemotherapy regimens including oxaliplatin. Novel precision medicine concepts based on preclinical models are lacking. A platform and biobank of rectal cancer organoids that recapitulates essential aspects of the response of rectal cancer to radiation and chemoradiation has already been established by us. This was used to perform combination screens with a total of 1596 drug-radiation combinations. Several drug targets have been identified that enhance radiosensitivity, including PARP or apoptosis pathways, while the drugs with the strongest synergistic effects were inhibitors of the MAPK/RAS-signaling pathway. Preliminary mechanistic studies revealed that irradiation could activate RAS signaling in colorectal cancer cell lines and MEK inhibitors interfered with this response. In addition, MAPK pathway inhibition could suppress specific knots of the cellular DNA repair response, which are activated upon radiation. Based on this preliminary work, our project aim is to (I) characterize the regulation of DNA repair genes by MEK inhibition and (II) decipher the genetic context of radiosensitivity to MAPK-pathway inhibition. Furthermore, synergistic drug combinations that further enhance radiosensitivity induced by MAPK pathway inhibition will be identified (III). Insights from these aims shall pave the way for a phase I trial of radiation plus MEK inhibitor combination therapy in rectal cancer patients.
dkfz.de
Radiosensitization by combined MAPK-inhibition in rectal cancer (RASCAL).
- Schematic overview of the rectal cancer organid platform to allow studying of mechanisms of radiation and MAPK/RAS inhibition in rectal cancer models.
- Immunofluorescence images of rectal cancer organoids undergoing control treatment (left) or MAPK/RAS pathway inhibition with MEK-inhibitor trametinib (right), cyan: nuclei, magenta: actin.
images from doi:10.1038/s41467-022-30722-9.