<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Screen of Compounds to Target Tumor Cells with Chromothripsis"^^ . "Chromothripsis is a form of genomic instability that begins with a shattering event leading to clustered \r\nchromosomal aberrations. Chromothriptic cells acquire multiple genomic alterations in confined genomic \r\nregions restricted to one or a few chromosomes. Due to the very high prevalence of chromothripsis in \r\ndifferent types of cancers especially Sonic Hedgehog medulloblastomas, osteosarcomas and \r\nneuroblastomas and due to the link between chromothripsis and poor prognosis for cancer patients, \r\nfinding therapeutic options to specifically target tumor cells with chromothripsis is highly relevant. \r\nChromothripsis is linked to homologous recombination (HR) repair deficiency in a number of tumor types. \r\nTherefore, synthetic lethality may potentially be used, whereby HR repair deficiencies of cancer cells are \r\nexploited by applying a PARP inhibitor, which spares repair-proficient normal cells. In the primary screen, \r\nI searched for potential additive or synergistic partners of a PARP inhibitor (BGB290) and also searched \r\nfor drugs that are potent as single agents. The analysis of the primary screen done in 15 cell lines \r\nidentified romidepsin and nanaomycin A as promising candidates to eliminate tumor cells with \r\nchromothripsis. To confirm the potential additivity or synergism of these drugs with the PARP inhibitor, \r\na secondary screen was done where drugs were titrated against each other in 8×8 matrix settings. The \r\nsecondary screen revealed a strong synergistic interaction between BGB290 and romidepsin in \r\nchromothriptic Sonic Hedgehog (SHH) medulloblastoma patient derived xenograft spheroid models but \r\nantagonism in non-chromothriptic control cells. Functional assays revealed that the synergistic effect \r\nbetween BGB290 and romidepsin was not TP53 dependent. Romidepsin and BGB290 combination \r\ntreatment caused G2 cell cycle arrest and apoptosis in chromothriptic DAOY cells. The mitotic rate was \r\ndecreased by romidepsin and BGB290 combination treatment in DAOY cells as shown by acetyl-αtubulin and phospho-histone H3 immunostaining. Gene expression analysis revealed that the romidepsin \r\nand BGB290 combination treatment was associated to the regulation of MYC target genes. To further \r\nanalyze the link between MYC expression and the effects of the combination treatment, I used an \r\ninducible MYC ON / OFF system. When MYC was overexpressed, romidepsin and BGB290 showed \r\nadditivity, while in the MYC OFF state the additive effect was replaced by antagonism. This indicates \r\nthat MYC overexpression plays a role in the interaction between BGB290 and romidepsin. Lastly, the in \r\nvivo efficacy of BGB290 and romidepsin combination treatment was confirmed in patient-derived \r\nxenograft mouse models."^^ . "2021" . . . . . . . "Umar"^^ . "Khalid"^^ . "Umar Khalid"^^ . . . . . . "Screen of Compounds to Target Tumor Cells with Chromothripsis (PDF)"^^ . . . "Thesis_Umar_Khalid.pdf"^^ . . . "Screen of Compounds to Target Tumor Cells with Chromothripsis (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Screen of Compounds to Target Tumor Cells with Chromothripsis (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Screen of Compounds to Target Tumor Cells with Chromothripsis (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Screen of Compounds to Target Tumor Cells with Chromothripsis (Other)"^^ . . . . . . "small.jpg"^^ . . . "Screen of Compounds to Target Tumor Cells with Chromothripsis (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #29959 \n\nScreen of Compounds to Target Tumor Cells with Chromothripsis\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . . . "610 Medizin"@de . "610 Medical sciences Medicine"@en . .