p38α kinase inhibition for the treatment of colorectal cancer

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URI: http://hdl.handle.net/10900/125296
Dokumentart: PhDThesis
Date: 2024-02-02
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Pharmazie
Advisor: Laufer, Stefan (Prof. Dr.)
Day of Oral Examination: 2022-02-02
DDC Classifikation: 500 - Natural sciences and mathematics
Other Keywords:
Colorectal cancer
organoid cultures
License: http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en
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p38α (Mapk14) is a member of the MAP kinase family and can be activated by environmental stress signaling and pro-inflammatory cytokines. Recent data suggest p38α as a potential target for the treatment of colitis-associated colorectal cancer (CRC). However, CRC that is linked to ulcerative colitis or to Crohn’s disease accounts for only a small subgroup of cases. In order to determine the therapeutic potential of p38α inhibition in colitis-independent colorectal cancer, I generated organoid-based CRC mouse models. Organoid cultures of murine colon epithelial cells were established and transformed in vitro by genetic modification of Apc, Kras and Trp53 using CRISPR/Cas9 and cre recombinase. Upon transformation, these cultures were re-transplanted into mice where they efficiently formed colorectal tumors. By seeding organoid CRC cells into the spleen, I was able to generate tumor formation in the liver in order to model CRC metastases. By using shRNA interference, I found that Mapk14/p38α represents an important factor in CRC development. However, treatment of organoid-based CRC models in vitro and in vivo with specific and well-established p38α inhibitors (Skepinone-L, PH797804), did not result in a pronounced therapeutic effect. Mechanistic studies revealed that increased activation of p38α kinase during therapy counteracts complete p38α pathway inhibition in CRC. To allow for a full blockade of p38α a signaling in colorectal cancer, I tested a novel class of type 1.5 p38α inhibitors with picomolar activity and substantially improved target residence time that were generated by the Laufer Lab. I applied these inhibitors in different CRC organoid cultures and detected a strong therapeutic response due to induction of DNA damage and an altered G2/M checkpoint leading to cell death. These compounds are well tolerated by mice and efficiently block CRC development in vivo. To determine the potential of novel p38α compounds with increased target residence time in human CRC, I generated a panel of patient-derived CRC organoid cultures. These cultures showed an initial resistance to standard chemotherapies and p38α inhibition with established inhibitors; however, strongly respond to a treatment with our new generation p38α inhibitors. Taken together, my data indicate that new generation p38α inhibitors with substantially improved target residence time have a therapeutic potential for the treatment of advanced colorectal cancer.

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