Cancer Therapeutics Insights Low Levels of Circulating Estrogen Sensitize PTEN-Null Endometrial Tumors to PARP Inhibition In Vivo

Earlier in vitrowork demonstrated that PARP inhibition induces cell death in PTEN-null endometrial cancer cell lines, but the in vivo therapeutic efficacy of these agents against endometrial cancer remains unknown. Here, we test the efficacy of AZD2281 (olaparib), an oral PARP inhibitor, in the therapy of PTEN-null endometrial tumors in a preclinical endometrial cancer mouse model. Primary endometrial tumors were generated by epithelial loss of PTEN using an in vivomodel. This model recapitulates epithelial-specific loss of PTEN seen in human tumors, and histologically resembles endometrioid carcinomas, the predominant subtype of human endometrial cancers. Olaparib was administered orally to tumor-bearing mice in two hormonal extremes: highor lowestrogen.Olaparib treatment achieveda significant reduction in tumor size in a low estrogenicmilieu. In striking contrast, no response to olaparibwas seen in tumors exposed to high levels of estrogen. Two key observations weremadewhen estrogen levels were dropped: (i) the serum concentration of olaparib was significantly increased, resulting in sustained PARP inhibition at the tumor bed; and (ii) the homologous recombination pathwaywas compromised, as evidenced by decreased Rad51 protein expression and function. These two mechanisms may account for the sensitization of PTEN-null tumors to olaparib with estrogen deprivation. Results of this preclinical trial suggest that orally administered PARP inhibitors in a low estrogenic hormonal milieu can effectively target PTEN-null endometrial tumors. Extension of this work to clinical trials could personalize the therapy of women afflicted with advanced endometrial cancer using well-tolerated orally administered therapeutic agents. Mol Cancer Ther; 12(12); 2917–28. 2013 AACR