TY  - GEN
ID  - heidok29959
AV  - public
CY  - Heidelberg
TI  - Screen of Compounds to Target Tumor Cells with Chromothripsis
Y1  - 2021///
N2  - Chromothripsis is a form of genomic instability that begins with a shattering event leading to clustered 
chromosomal aberrations. Chromothriptic cells acquire multiple genomic alterations in confined genomic 
regions restricted to one or a few chromosomes. Due to the very high prevalence of chromothripsis in 
different types of cancers especially Sonic Hedgehog medulloblastomas, osteosarcomas and 
neuroblastomas and due to the link between chromothripsis and poor prognosis for cancer patients, 
finding therapeutic options to specifically target tumor cells with chromothripsis is highly relevant. 
Chromothripsis is linked to homologous recombination (HR) repair deficiency in a number of tumor types. 
Therefore, synthetic lethality may potentially be used, whereby HR repair deficiencies of cancer cells are 
exploited by applying a PARP inhibitor, which spares repair-proficient normal cells. In the primary screen, 
I searched for potential additive or synergistic partners of a PARP inhibitor (BGB290) and also searched 
for drugs that are potent as single agents. The analysis of the primary screen done in 15 cell lines 
identified romidepsin and nanaomycin A as promising candidates to eliminate tumor cells with 
chromothripsis. To confirm the potential additivity or synergism of these drugs with the PARP inhibitor, 
a secondary screen was done where drugs were titrated against each other in 8×8 matrix settings. The 
secondary screen revealed a strong synergistic interaction between BGB290 and romidepsin in 
chromothriptic Sonic Hedgehog (SHH) medulloblastoma patient derived xenograft spheroid models but 
antagonism in non-chromothriptic control cells. Functional assays revealed that the synergistic effect 
between BGB290 and romidepsin was not TP53 dependent. Romidepsin and BGB290 combination 
treatment caused G2 cell cycle arrest and apoptosis in chromothriptic DAOY cells. The mitotic rate was 
decreased by romidepsin and BGB290 combination treatment in DAOY cells as shown by acetyl-?tubulin and phospho-histone H3 immunostaining. Gene expression analysis revealed that the romidepsin 
and BGB290 combination treatment was associated to the regulation of MYC target genes. To further 
analyze the link between MYC expression and the effects of the combination treatment, I used an 
inducible MYC ON / OFF system. When MYC was overexpressed, romidepsin and BGB290 showed 
additivity, while in the MYC OFF state the additive effect was replaced by antagonism. This indicates 
that MYC overexpression plays a role in the interaction between BGB290 and romidepsin. Lastly, the in 
vivo efficacy of BGB290 and romidepsin combination treatment was confirmed in patient-derived 
xenograft mouse models.
A1  - Khalid, Umar
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/29959/
ER  -