• Ursula Kortmann, Jessica N McAlpine, Hui Xue, Jun Guan, Gavin Ha, Sophie Tully, Sharaz Shafait, Alan Lau, Aaron N Cranston, Mark J O'Connor, David G Huntsman, Yuzhuo Wang, and C Blake Gilks.
• Department of Pathology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada.
• Clin Cancer Res. 2011 Feb 15; 17 (4): 783-91.

PurposeMost patients with ovarian carcinomas succumb to their disease and there is a critical need for improved therapeutic approaches. Carcinomas arising in BRCA mutation carriers display defective DNA double-strand break repair that can be therapeutically exploited by inhibition of PARP-1, a key enzyme in the repair of DNA single-strand breaks, creating synthetic lethality in tumor cells.Experimental DesignTo investigate synthetic lethality in vivo, we established a BRCA2 germline-mutated xenograft model that was developed directly from human ovarian cancer tissue, treated with the PARP inhibitor olaparib (AZD2281) alone and in combination with carboplatin.ResultsWe show that olaparib alone and in combination with carboplatin greatly inhibit growth in BRCA2-mutated ovarian serous carcinoma. This effect was not observed in a serous carcinoma with normal BRCA function, showing a specific antitumor effect of olaparib in mutation carriers. Immunohistochemistry (cleaved caspase-3 and Ki-67 stains) of remnant tissue after olaparib treatment revealed significantly decreased proliferation and increased apoptotic indices in these tumors compared with untreated controls. Furthermore, olaparib-treated tumors showed highly reduced PARP-1 activity that correlated with olaparib levels.ConclusionsWe established a BRCA2-mutated human ovarian cancer xenograft model suitable for experimental drug testing. The demonstrated in vivo efficacy of olaparib extends on the preclinical rationale for further clinical trials targeting ovarian cancer patients with BRCA mutations.©2010 AACR.

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