Poly (Adp) Ribose Polymerase Inhibitors For The Treatment Of Malignant Peripheral Nerve Sheath Tumor
Date of Graduation
5-2016
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Keila E. Torres, MD, PhD
Committee Member
Robert C. Bast Jr., MD
Committee Member
David J. McConkey, PhD
Committee Member
Rosemarie E. Schmandt, PhD
Committee Member
Subrata Sen, PhD
Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a rare subtype of soft tissue sarcoma. Surgical excision has remained the standard of care for this highly aggressive malignancy for over a decade. Conventional chemotherapy and radiotherapy have shown limited efficacy in MPNST; therefore, it is imperative that targeted treatment be identified to improve the outcome for MPNST patients. Poly (ADP) ribose polymerase (PARP) inhibitors were first reported over a decade ago to have substantial anti-tumorigenic effects in malignancies with defective DNA repair, specifically those with BRCA1/2 (breast cancer, early onset 1/2) mutations. Further evaluation of these inhibitors has shown multiple mechanisms of sensitivity, all of which are associated with the DNA damage response and DNA repair. While no specific defects in DNA repair machinery have been reported in MPNST, sensitivity to PARP inhibition may be predicted by its complex karyotype and inherent genomic instability. We show increased PARP1 and PARP2 expression in MPNST patient tumor samples and increased PARP activity in cell lines. We also demonstrate the anti-MPNST effect of the PARP inhibitor AZD2281 in vitro and in vivo. Specifically, decreased cell proliferation and induction of apoptosis were observed in MPNST cell lines at AZD2281 doses and time points similar to, or less than, those used in cells lines with known DNA repair defects. In addition, AZD2281 treatment suppressed MPNST subcutaneous xenograft growth and lung metastasis progression, and increased survival times of mice with metastatic disease. Upon investigation of a potential mechanism of sensitivity, we found decreased efficacy of homologous recombination (HR) and increased activity of non-homologous end joining (NHEJ) in MPNST cell lines, suggesting a potential mechanism of sensitivity to PARP inhibition due to increased genomic instability. We also observed decreased expression of Cockayne syndrome B (CSB), a pivotal member of the transcription coupled repair (TCR) pathway. Subsequent overexpression of CSB decreased the sensitivity of a subset of MPNST cell lines to AZD2281 treatment. Our results suggest that PARP is a valuable anti-MPNST target and that sensitivity could be due to defective DNA repair pathways. Moreover, AZD2281 should be evaluated for its efficacy as a therapeutic agent for MPNST patients.
Keywords
Malignant peripheral nerve sheath tumor, soft tissue sarcoma, poly (ADP) ribose polymerase, PARP, MPNST, PARP inhibitor, DNA repair