Accession Number : AD1048457


Title :   Identifying Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer


Descriptive Note : Technical Report,15 Sep 2016,14 Sep 2017


Corporate Author : The Research Institute of Fox Chase Cancer Center Philadelphia United States


Personal Author(s) : Johnson, Neil


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1048457.pdf


Report Date : 01 Oct 2017


Pagination or Media Count : 12


Abstract : Cells that are deficient in homologous recombination (HR) DNA repair, such as those lacking functional BRCA1 are highly sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Ovarian cancer patients that harbored germ-line BRCA1 mutations treated with PARP inhibitors exhibited meaningful responses in early phase clinical trials. However, emerging clinical trial data indicates that PARP inhibitor therapy may benefit only a subset of BRCA1 mutation carriers. In this reporting period, we have identified genetic alterations in PARP inhibitor resistant cell lines using whole exome analyses and RNA-seq technologies. We used MDA-MB-436, HCC1395, UWB1.289 and SUM149 cell lines that all harbor BRCA1 mutations to analyze parental PARP inhibitor sensitive and resistant derivatives for gene expression and mutational changes. We identified PHC2, ARID1B, ANKLE1, CHL1 genes that had recurring mutations in PARP inhibitor resistant cell lines. In gene expression analyses, we identified PHC2, ARID1B, ANKLE1, CHL1, BST2, ASNS, EHF genes that had recurring altered expression in PARP inhibitor resistant cells. The next steps of our research will be to use siRNA to alter the expression of the genes identified and determine if they impact PARP inhibitor sensitivity and DNA repair pathways.


Descriptors :   ovarian cancer , genes , inhibitors , platinum , biological markers , drug resistance , mutations , clinical trials , cell line , Rna sequence analysis , gene expression , deoxyribonucleic acids , ribonucleic acids , proteins , neoplasms


Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology
      Biochemistry


Distribution Statement : APPROVED FOR PUBLIC RELEASE