title: Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor.
abstract: Poly (ADP) ribose polymerase (PARP) inhibitors, first evaluated nearly a decade ago, are primarily used in malignancies with known defects in DNA repair genes, such as alterations in breast cancer, early onset 1/2 (BRCA1/2). While no specific mutations in BRCA1/2 have been reported in malignant peripheral nerve sheath tumors (MPNSTs), MPNST cells could be effectively targeted with a PARP inhibitor to drive cells to synthetic lethality due to their complex karyotype and high level of inherent genomic instability. In this study, we assessed the expression levels of PARP1 and PARP2 in MPNST patient tumor samples and correlated these findings with overall survival. We also determined the level of PARP activity in MPNST cell lines. In addition, we evaluated the efficacy of the PARP inhibitor AZD2281 (Olaparib) in MPNST cell lines. We observed decreased MPNST cell proliferation and enhanced apoptosis in vitro at doses similar to, or less than, the doses used in cell lines with established defective DNA repair genes. Furthermore, AZD2281 significantly reduced local growth of MPNST xenografts, decreased the development of macroscopic lung metastases, and increased survival of mice with metastatic disease. Our results suggest that AZD2281 could be an effective therapeutic option in MPNST and should be further investigated for its potential clinical use in this malignancy.
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.|b The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kivlin
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Watson
authors.affiliation: c Department of Pathology and Genomic Medicine , Houston Methodist Hospital , Houston , TX , USA.
authors.forename: Ghadah A
authors.initials: GA
authors.lastname: Al Sannaa
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Belousov
authors.affiliation: d Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Davis R
authors.initials: DR
authors.lastname: Ingram
authors.affiliation: b The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center , Houston , TX , USA.|e Department of Biochemistry and Molecular Biology , The University of Texas-Medical School , Houston , TX , USA.
authors.forename: Kai-Lieh
authors.initials: KL
authors.lastname: Huang
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.|b The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Caitlin D
authors.initials: CD
authors.lastname: May
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Landers
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Azad Abul
authors.initials: AA
authors.lastname: Kalam
authors.affiliation: f Department of Neuro-Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Slopis
authors.affiliation: g Department of Neurosurgery , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Ian E
authors.initials: IE
authors.lastname: McCutcheon
authors.affiliation: h Department of Surgery , The Ohio State University, Wexner Medical Center , Columbus , OH , USA.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.affiliation: i Department of Surgery , Sheba Medical Center, Tel Aviv University , Tel Aviv , Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.affiliation: b The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center , Houston , TX , USA.|d Department of Pathology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.|b The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Keila E
authors.initials: KE
authors.lastname: Torres
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009442:Neurilemmoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000096:biosynthesis / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: AZD2281 (Olaparib); PARP inhibitor; malignant peripheral nerve sheath tumor (MPNST); poly (ADP) ribose polymerase (PARP); soft tissue sarcoma