The addition of temozolomide (TMZ) during and after radiation therapy improves survival for patients with newly diagnosed GBM and is the current standard of care. However, the survival benefit of TMZ therapy is limited by the development of TMZ resistance in the majority of patients, and there is significant interest in identifying molecular sensitizing strategies to improve the efficacy of TMZ. One promising strategy targeting the repair of TMZ-induced DNA damage is inhibition of poly-ADP-ribose polymerase (PARP). PARP is indirectly involved in numerous repair pathways, and multiple preclinical studies have demonstrated significant enhancement of TMZ efficacy in various tumor models. Previously published studies suggest that PARP inhibitors disrupt base-excision repair (BER) of TMZ-induced DNA methylation lesions and suggest that essentially all tumors would be sensitized to TMZ by PARP inhibition through disruption of this repair process. In contrast, in our preliminary studies using paired sensitive parental and derived TMZ resistant xenograft lines, we demonstrate that the PARP inhibitor ABT-888 effectively sensitizes only tumors that are inherently sensitive to TMZ. Aside from potential effects on BER, PARP has critical functions in post-replication repair (PRR) of stalled replication forks, and from these observations, we hypothesize that PARP inhibitors will enhance the efficacy of TMZ in GBM tumors that are inherently sensitive to TMZ and that disruption of PRR processing of persistent methylation damage is critical to this effect. These observations have significant clinical implications for the development of PARP inhibitor strategies. The focus of this application is to test these interconnected hypotheses using TMZ and 2 structurally distinct PARP inhibitors to optimize clinical development of PARP inhibitor strategies.
The specific aims of this application are:
Specific Aim 1 : Identify the most efficacious sequence and schedule for combined therapy of temozolomide and PARP inhibitors.
Specific Aim 2 : Investigate the relative importance of MGMT/MMR status and inherent TMZ sensitivity for the sensitizing effects of PARP inhibitors.
Specific Aim 3 : Evaluate the importance of PARP-mediated effects on recovery of stalled replication forks versus base-excision repair.
The development of effective chemo-sensitizing strategies could significantly improve the survival of patients with GBM. PARP inhibitors show significant promise as a specific TMZ-sensitizing strategy. In this proposal, we will use a panel of primary GBM xenograft lines in a series of experiments that will provide critical insight into optimal clinical development of this sensitizing strategy.
|Parrish, Karen E; Cen, Ling; Murray, James et al. (2015) Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System. Mol Cancer Ther 14:2735-43|
|Pokorny, Jenny L; Calligaris, David; Gupta, Shiv K et al. (2015) The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma. Clin Cancer Res 21:1916-24|
|Gupta, Shiv K; Mladek, Ann C; Carlson, Brett L et al. (2014) Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts. Clin Cancer Res 20:3730-41|
|Cen, Ling; Carlson, Brett L; Pokorny, Jenny L et al. (2013) Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models. Neuro Oncol 15:735-46|
|Kitange, Gaspar J; Mladek, Ann C; Carlson, Brett L et al. (2012) Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts. Clin Cancer Res 18:4070-9|
|Nadkarni, Aditi; Shrivastav, Meena; Mladek, Ann C et al. (2012) ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells. J Neurooncol 110:349-57|