Earlier 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 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 vivo model. 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: 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: (i) the serum concentration of
olaparib was significantly increased, resulting in sustained PARP inhibition at the
tumor bed; and (ii) the homologous recombination pathway was 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.