Abstract 5539: Low levels of estrogen sensitize PTEN-deficient endometrial tumors to poly-ADP ribose polymerase (PARP) inhibition in vivo.
Authors: Paik Daniel Y. , Rosales Miguel , Janzen Deanna , Yep Brian , Cheng Donghui , Witte Owen , Kayadibi Huseyin , Faull Kym , Memarzadeh Sanaz 
Published: August 2014

Abstract
Prior in vitro work suggests that PARP inhibition can destroy tumor cells with defects in homologous recombination resulting from loss of PTEN. Clinical trials have tested the efficacy of this strategy in BRCA mutant ovarian tumors. This approach has not been reported in endometrial carcinomas in vivo. Loss of PTEN tumor suppressor function is the most common genetic alteration associated with endometrial cancer that is the leading gynecologic cancer in the U.S. We hypothesized that oral administration of the PARP inhibitor AZD2281 (Olaparib) would be an effective therapeutic strategy for treating endometrial carcinomas resulting from PTEN loss. This hypothesis was tested in a mouse model for endometrial cancer established by our group. Uterine epithelia were harvested from PTENloxP/loxP mice, dissociated and infected with a Cre lentivirus resulting in PTEN deletion in uterine epithelia. These cells were combined with wild type stroma and placed subrenally in SCID mice resulting in formation of endometrial tumors that accurately recapitulate human disease. After tumor establishment (8 weeks), mice were divided into two cohorts: Group 1 was subjected to a continuous supply of estrogen and Group 2 was deprived of estrogen. Ten SCID mice were treated with a PARP inhibitor, AZD2281, administered orally for 3 weeks while the other 10 SCID mice were treated with vehicle in both hormonal conditions. At completion of therapy, tumors were harvested and analyzed. Forty mice were included in this preclinical trial. AZD2281 was successful in achieving a significant reduction in tumor size in a low estrogenic hormonal milieu. In striking contrast, no response to AZD2281 was seen in tumors exposed to high levels of estrogen. Hormonal deprivation resulted in a 20-fold increase in circulating levels of AZD2281 concomitant with increased inhibition of PARP enzyme activity at the tumor bed. Low levels of estrogen sensitize PTEN deficient tumors to PARP inhibition via two potential mechanisms: 1) down-regulation of key components of the homologous recombination pathway in low compared to high levels of estrogen and 2) a significant increase in the serum concentration of AZD2281 coupled with increased efficacy of PARP inhibition at the tumor bed. We suspect that withdrawal of estrogen results in a decrease in homologous recombination proteins and an increase in circulating levels of AZD2281 by decreasing its metabolism. The net result is greater circulating levels and effectiveness of PARP inhibitors in estrogen deprived treated mice. The results of this preclinical trial suggest that orally administered PARP inhibitors in a low estrogenic hormonal milieu can be effective in targeting PTEN-null endometrial tumors. Extension of this work to a clinical trial can result in personalizing therapies for women afflicted with endometrial cancer using well tolerated orally administered therapeutic agents.
Citation Format: Daniel Y. Paik, Miguel Rosales, Deanna Janzen, Brian Yep, Donghui Cheng, Owen Witte, Huseyin Kayadibi, Kym Faull, Sanaz Memarzadeh. Low levels of estrogen sensitize PTEN-deficient endometrial tumors to poly-ADP ribose polymerase (PARP) inhibition in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5539. doi:10.1158/1538-7445.AM2013-5539