Abstract 3947: PARP-1 as a therapeutic target in gliomas

Abstract

Abstract Gliomas are the most common primary tumors in the brain. We use this tumor type as a paradigm of oncogenic transformation. Deregulation of signal transduction pathways are commonly found both in low- and high-grade gliomas. Moreover, all WHO grade III and IV (GBM) show a disruption of cell cycle due to alterations in at least one out of three families of proteins involved in G1/S transition, such as: CDKs, INK4a-ARF or Rb. Oncogenic HRas (HRasV12) expression recapitulates gain-of-function mutations in several growth factor receptors in glial cells, resulting in the activation of different downstream effectors such as Raf/MEK/ERK and PI3K/AKT signaling pathways. The hyperactivation of growth signaling pathways, phenocopied by HRasV12, increases cell proliferation rate in the absence of senescence, facilitating their transformation into tumoral cells. Furthermore, our data indicate that HRasV12 is able to cooperate with Rb loss in the tumor malignization. Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of DNA damage. Despite its important role in the cellular response to genotoxic stress, PARP-1 is not required for survival and Parp-1−/− mice are viable and fertile. These mice do not develop early onset tumors and tumor latency is increased in PARP-1 knockout mice that are deficient for p53. Accordingly, here we observed that Parp-1−/− astrocytes display a marked proliferative decrease when compared with Parp-1+/+ astrocytes which express HRasV12, either in a Rb+/+ or in a Rb−/− context. Given that loss of PARP-1 are less susceptible to HRasV12 induced transformation, the inactivation of PARP-1 with chemical inhibitors is a potential therapeutic approach to restrain the tumor progression. Interestingly, in our model of gliomagenesis PARP-1 chemical inhibition (PJ34) leads to a significant fall in the proliferative rate in HRasV12 astrocytes comparable to Parp-1−/− astrocytes, and is also able to reduce tumor progression even when HRasV12 cooperates with Rb loss. These results indicate that treatment with PARP-1 inhibitors might be a potential therapy for this type of tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3947.