FOR2314

TP01: Charakterisierung des ribosomalen Proteins Rpl15 als therapeutische Zielstruktur zur Behandlung des hepatozellulären Karzinoms

01/08/2015 to 31/07/2018

Hepatocellular carcinoma (HCC) represents a particularly aggressive and therapy resistant tumor
type, for which new treatment approaches are urgently needed. A direct in vivo shRNA screen
identified the 60S ribosomal large subunit protein L15 (RPL15) as a new therapeutic target for
HCC treatment. Preliminary data underlying this project revealed that even short term inhibition of
the ribosomal protein 15 triggers a robust cellular senescence response, designated ribosomal
checkpoint induced senescence (RCIS), in aggressive liver cancer cells but only a reversible cell
cycle arrest in normal cells. ShRNA mediated suppression of Rpl15 in orthotopically and
autochthonously grown aggressive murine liver carcinomas allowed for long term tumor control
and we are now proposing to mechanistically explore and therapeutically develop Rpl15 as a
therapeutic target for the treatment of therapy resistant HCC and other solid tumors.
We aim to further dissect the mechanisms underlying RCIS induction, with a particular emphasis
on Myc- and p53 dependent pathways. Furthermore, we will assess qualitative changes in mRNA
translation upon RCIS (ribsome footprinting) and seek to identify targetable vulnerabilities in tumor
cells which underwent RCIS. To model potential side effects of Rpl15 inhibition towards normal
tissues we recently generated Rpl15 shRNA transgenic mice, which allow for a tet-regulatable
conditional Rpl15 knockdown in all tissues and are thus ideally suited to mimick the action of a
systemic pharmacological Rpl15 inhibition. Taking advantage of these mice, we will apply
ubiquitous shRNA expression in tumor bearing mice and conduct preclinical treatment studies
using maximum tolerable metronomic treatment intervals. As it has been shown that cancer cells
harbour both quantitative as well as qualitative alterations in protein translation, we will furthermore
apply direct in vivo RNAi screening to systematically probe all known factors involved in ribosome
biogenesis and translation (including all ribosomal proteins, translation initiation factors, RNA
polymerase I and III) in order to unveil further vulnerabilities within the translation apparatus of
cancer cells which might be exploited for cancer therapy