Poly (ADP) ribose polymerase inhibition

A potential treatment of malignant peripheral nerve sheath tumor

Christine M. Kivlin, Kelsey L. Watson, Ghadah A. Al Sannaa, Roman Belousov, Davis R. Ingram, Kai-Lieh Huang, Caitlin D. May, Svetlana Bolshakov, Sharon M. Landers, Azad Abul Kalam, John M. Slopis, Ian E. McCutcheon, Raphael E. Pollock, Dina Lev, Alexander J. Lazar, Keila E. Torres

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)129-138
Number of pages10
JournalCancer Biology and Therapy
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Neurilemmoma
Therapeutics
Tumor Cell Line
DNA Repair
Breast Neoplasms
Neoplasms
Genomic Instability
Karyotype
Heterografts
Genes
Cell Proliferation
Apoptosis
Neoplasm Metastasis
Cell Line
Lung
Mutation
Survival
olaparib
Growth

Keywords

  • AZD2281 (Olaparib)
  • malignant peripheral nerve sheath tumor (MPNST)
  • PARP inhibitor
  • poly (ADP) ribose polymerase (PARP)
  • soft tissue sarcoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Poly (ADP) ribose polymerase inhibition : A potential treatment of malignant peripheral nerve sheath tumor. / Kivlin, Christine M.; Watson, Kelsey L.; Al Sannaa, Ghadah A.; Belousov, Roman; Ingram, Davis R.; Huang, Kai-Lieh; May, Caitlin D.; Bolshakov, Svetlana; Landers, Sharon M.; Kalam, Azad Abul; Slopis, John M.; McCutcheon, Ian E.; Pollock, Raphael E.; Lev, Dina; Lazar, Alexander J.; Torres, Keila E.

In: Cancer Biology and Therapy, Vol. 17, No. 2, 01.02.2016, p. 129-138.

Research output: Contribution to journalArticle

Kivlin, CM, Watson, KL, Al Sannaa, GA, Belousov, R, Ingram, DR, Huang, K-L, May, CD, Bolshakov, S, Landers, SM, Kalam, AA, Slopis, JM, McCutcheon, IE, Pollock, RE, Lev, D, Lazar, AJ & Torres, KE 2016, 'Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor', Cancer Biology and Therapy, vol. 17, no. 2, pp. 129-138. https://doi.org/10.1080/15384047.2015.1108486
Kivlin, Christine M. ; Watson, Kelsey L. ; Al Sannaa, Ghadah A. ; Belousov, Roman ; Ingram, Davis R. ; Huang, Kai-Lieh ; May, Caitlin D. ; Bolshakov, Svetlana ; Landers, Sharon M. ; Kalam, Azad Abul ; Slopis, John M. ; McCutcheon, Ian E. ; Pollock, Raphael E. ; Lev, Dina ; Lazar, Alexander J. ; Torres, Keila E. / Poly (ADP) ribose polymerase inhibition : A potential treatment of malignant peripheral nerve sheath tumor. In: Cancer Biology and Therapy. 2016 ; Vol. 17, No. 2. pp. 129-138.
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