Low levels of circulating estrogen sensitize PTEN-null endometrial tumors to PARP inhibition in vivo.
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.
Corresponding Author: Sanaz Memarzadeh, University of California, Los Angeles, 555 Westwood Plaza, Level B, Box 957243, 1015 Terasaki Life Sciences Building, Los Angeles, CA 90095. smemarzadeh@mednet.ucla.edu.
Deanna M
DM
Janzen
Daniel Y
DY
Paik
Miguel A
MA
Rosales
Brian
B
Yep
Donghui
D
Cheng
Owen N
ON
Witte
Huseyin
H
Kayadibi
Christopher M
CM
Ryan
Michael E
ME
Jung
Kym
K
Faull
Sanaz
S
Memarzadeh
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000097:blood*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D004967:Estrogens; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D051135:Rad51 Recombinase; D051059:PTEN Phosphohydrolase; C531550:olaparib