Abstract 5497: An inhibitor of phosphatase PP2A enhances in vivo anticancer activity of a phospho (ADP-ribosyl) polymerase inhibitor (PARPi) combined with temozolomide (TMZ)

We previously showed that a novel inhibitor of PP2A enhances the in vivo activity of TMZ against human glioblastoma xenografts (Lu et al, PNAS 2009;104:11697-11702). Several mechanisms underlie this effect of PP2A inhibition and include an increased rate of cancer cell entry into DNA synthesis, inhibition of cell cycle arrest at G1 and G2/M, and a marked reduction in p53. Because inhibitors of PARP1 have been shown to enhance the activity of cytotoxic cancer drugs by inhibiting repair of single-strand breaks in cells with impaired mechanisms for double-stranded DNA repair (BrCa mutants, triple negative breast cancer cells), we reasoned that blocking other types of DNA-damage defense mechanisms by PP2A inhibition might further enhance the activity of a PARPi combined with TMZ in cancers, not necessarily already deficient in DNA repair. We treated mice bearing xenografts of human melanoma, line A2058, with single agent LB-100, a novel water soluble PP2A inhibitor (Lixte Biotechnology Holdings, Inc., East Setauket, NY; Lu et al, J Neurosurg 2010; 113: 225-233) at 1.5mg/kg by continuous intraperitoneal (i.p.) infusion for 21 days and TMZ at 80mg/kg i.p. days 3,6,9,12,15,18. LB-100 and TMZ were given alone and in combination with each other and in 2-drug combinations with the PARPi, ABT-888 (Sigma), at 6.25 mg/kg i.p. on days 3,6,9,12,15,18, and all three drugs were given together at the same doses and schedules as when used alone or in 2-drug combinations. (ABT-888 was inactive as a single agent and was not used alone). The combination of LB-100 + TMZ was more inhibitory to the xenografts at 21 days than ABT-888 + TMZ, but the 3-drug regimen was most effective and no more toxic than any of the 2-drug regimens. Histologic analysis of xenografts 24 hours after treatment of animals with each of the single agents, each 2-drug regimen, and the 3-drug regimen showed increased apoptosis and necrosis by the 3-drug combination compared to the two-drug regimens, which in turn were more effective that the single agents. Similar results were found in vitro by flow cytometric analysis of A2058 cells 24 hours after exposure to the single agent and 2- and 3-drug regimens. Inclusion of a PP2A inhibitor may increase and extend the effectiveness of cytotoxic regimens containing a PARPi to cancers without acquired mutations in DNA repair. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5497. doi:10.1158/1538-7445.AM2011-5497