Data from Tumor Growth Inhibition by Olaparib in <i>BRCA2</i> Germline-Mutated Patient-Derived Ovarian Cancer Tissue Xenografts

Abstract

<div>Abstract<p><b>Purpose:</b> Most patients with ovarian carcinomas succumb to their disease and there is a critical need for improved therapeutic approaches. Carcinomas arising in <i>BRCA</i> 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.</p><p><b>Experimental Design:</b> To investigate synthetic lethality <i>in vivo</i>, we established a <i>BRCA2</i> 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.</p><p><b>Results:</b> We show that olaparib alone and in combination with carboplatin greatly inhibit growth in <i>BRCA2</i>-mutated ovarian serous carcinoma. This effect was not observed in a serous carcinoma with normal <i>BRCA</i> 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.</p><p><b>Conclusions:</b> We established a <i>BRCA2</i>-mutated human ovarian cancer xenograft model suitable for experimental drug testing. The demonstrated <i>in vivo</i> efficacy of olaparib extends on the preclinical rationale for further clinical trials targeting ovarian cancer patients with <i>BRCA</i> mutations. <i>Clin Cancer Res; 17(4); 783–91. ©2010 AACR.</i></p></div>