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

Abstract

Prior in vitro work 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 therapy of PTEN-null endometrial tumors in a pre-clinical endometrial cancer mouse model. Primary endometrial tumors were generated by epithelial loss of PTEN using an in vivo model. This model recapitulates epithelial specific loss of PTEN seen in human tumors and histologically resembles endometrioid carcinomas, the predominant sub-type of human endometrial cancers. Olaparib was administered orally to tumor bearing mice in two hormonal extremes: high or low estrogen. Olaparib treatment achieved a significant reduction in tumor size in a low estrogenic milieu. In striking contrast, no response to Olaparib was seen in tumors exposed to high levels of estrogen. Two key observations were made when estrogen levels were dropped. Serum concentration of Olaparib was significantly increased resulting in sustained PARP inhibition at the tumor bed. The homologous recombination pathway was compromised evidenced by decreased Rad51 protein and function. These two mechanisms may account for the sensitization of PTEN-null tumors to Olaparib with estrogen deprivation. Results of this pre-clinical 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.

Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung Cancer—Response

“…However, even among cancers with PTEN loss, there are likely to be additional factors that impact sensitivity, as suggested by a recent study that showed sensitivity of tumors with PTEN loss was dependent on levels of circulating estrogen (4). Furthermore, the potential benefit of dual PARP-PI3K pathway inhibition has also been suggested in breast cancer based on preclinical models of triple negative and BRCA mutated breast cancers (5) and is being explored in an ongoing clinical trial.…”

The role of poly(ADP-ribose) polymerase inhibitors in the treatment of endometrial cancer: a scoping review of the current literature

“…Of the studies selected for analysis, 4 were in vitro [14,[32][33][34], 2 were in vivo [35,36], 6 were reviews [3,7,[37][38][39][40], and 5 were clinical trials.…”

“…In total, 69 articles were evaluated and 17 were chosen for inclusion in the review. The sensitivity of the tumor to PARP inhibition may be altered by the hormonal milieu of the tumor [36]. In an in vivo study by Janzen et al, in a high estrogen state, peak olaparib concentrations, comparable to serum concentrations in humans treated with the common dose of 400 mg olaparib twice daily, were achieved at 2 hours.…”

“…Janzen et al, using PTEN-null endometrial cancer mouse model, evaluated the efficacy of the PARP inhibitor, olaparib, at low and high estrogen concentrations, done to recapitulate the hyperestrogenic state, secondary to obesity, found in most patients with endometrial cancer [36]. Tumors in oophorectomized mice kept in a low estrogen state had a six-fold decrease in tumor size when treated with olaparib, in contrast to no response to olaparib in mice exposed to high estrogen levels.…”

Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

“…12 Animals were treated with PARP inhibitors (10 mg/kg, injected i.p.) [13][14][15] for 2 hours prior to TNFα or lipopolysaccharaide (LPS) administration. Time window and concentrations for PARP inhibitor administration were based on the published literature [13][14][15] and experimental trial (data not shown).…”