Chemotherapy reduces PARP1 in cancers of the ovary: implications for future clinical trials involving PARP inhibitors.
BACKGROUND
PARP inhibitors have shown promising clinical results in cancer patients carrying BRCA1/2 mutations. Their clinical efficacy could logically be influenced by PARP1 protein levels in patient tumors.


METHODS
We screened three cohorts of patients with ovarian cancer, totaling 313 samples, and evaluated PARP1 protein expression by immunohistochemistry with further validation by western blotting.


RESULTS
We observed that up to 60 % of tumors showed little PARP1 protein expression. In serous ovarian tumors, comparing intratumoral PARP1 expression between chemo-naïve and post-chemotherapy patients revealed a decrease in intratumoral PARP1 following chemotherapy in all three cohorts (immunohistochemistry: p < 0.001, n = 239; western blot: p = 0.012, n = 74). The findings were further confirmed in a selection of matched samples from the same patients before and after chemotherapy.


CONCLUSIONS
Our data suggest that patients should be screened for PARP1 expression prior to therapy with PARP inhibitors. Further, the observed reduction of intratumoral PARP1 post-chemotherapy suggests that treating chemo-naïve patients with PARP inhibitors prior to the administration of chemotherapy, or concurrently, might increase the responsiveness to PARP1 inhibition. Thus, a change in the timing of PARP inhibitor administration may be warranted for future clinical trials.
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste, Catherine Road, Montréal, QC, H3T 1E2, Canada. maud.marques@mail.mcgill.ca.
Maud
M
Marques
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste, Catherine Road, Montréal, QC, H3T 1E2, Canada. mclaude13@hotmail.com.
Marie-Claude
MC
Beauchamp
Centre de recherche du Centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montréal, Canada. fleury.hu@gmail.com.
Hubert
H
Fleury
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste, Catherine Road, Montréal, QC, H3T 1E2, Canada. idolaskov@yahoo.com.|Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montréal, Canada. idolaskov@yahoo.com.
Ido
I
Laskov
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste, Catherine Road, Montréal, QC, H3T 1E2, Canada. sqtjcn@gmail.com.
Sun
S
Qiang
Division of Pathology, Jewish General Hospital, Montréal, Canada. manuela.pelmus@jgh.ca.
Manuela
M
Pelmus
Centre de recherche du Centre hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montréal, Canada. diane.provencher@umontreal.ca.|Department of Obstetric-Gynecology, Université de Montréal, Montreal, Canada. diane.provencher@umontreal.ca.|Department of Medicine, Université de Montréal, Montreal, Canada. diane.provencher@umontreal.ca.
Diane
D
Provencher
Department of Obstetric-Gynecology, Université de Montréal, Montreal, Canada. anne-marie.mes-masson@umontreal.ca.|Department of Medicine, Université de Montréal, Montreal, Canada. anne-marie.mes-masson@umontreal.ca.
Anne-Marie
AM
Mes-Masson
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste, Catherine Road, Montréal, QC, H3T 1E2, Canada. walter.gotlieb@mcgill.ca.|Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montréal, Canada. walter.gotlieb@mcgill.ca.
Walter H
WH
Gotlieb
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Ste, Catherine Road, Montréal, QC, H3T 1E2, Canada. michael.witcher@mcgill.ca.
Michael
M
Witcher
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases