O6-methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined.
We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens.
Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% +/- 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% +/- 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location.
Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.
"Without MGMT repair, O6-methylguanine initiates activation of mismatch repair-deficient (MMR) proteins or Rad3-related protein kinase that ultimately leads to apoptotic cell death (Caporali et al., 2004; Wang and Edelmann, 2006; Roos et al., 2007). High expression of MGMT or loss of MMR contributes significantly to TMZ resistance in many clinical cases (Pollack et al., 2006; Hegi et al., 2008; Sarkaria et al., 2008). The initiation of apoptotic signaling fails in the absence of the MMR system. "
[Show abstract][Hide abstract] ABSTRACT: Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor. Loss of gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.
Frontiers in Oncology 03/2013; 3:43. DOI:10.3389/fonc.2013.00043
"Abnormalities of p53 were most commonly seen in WHO grade IV tumors; however, p53 was shown to be an independent prognostic factor regardless of histologic grade (Pollack et al., 2002). A follow-up analysis of O6-methylguanine- DNA methyltransferase (MGMT) status in this same group of patients revealed a statistically worse outcome in children with overexpression of MGMT (Pollack et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: High grade gliomas (HGG) are one of the most common central nervous system (CNS) tumors encountered in adults, but they only represent approximately 8-12% of all pediatric CNS tumors. Historically, pediatric HGG were thought to be similar to adult HGG since they appear histologically identical; however, molecular, genetic, and biologic data reveal that they are distinct. Similar to adults, pediatric HGG are very aggressive and malignant lesions with few patients achieving long-term survival despite a variety of therapies. Initial treatment strategies typically consist of a gross total resection (GTR) when feasible followed by focal radiotherapy combined with chemotherapy. Over the last few decades, a wealth of data has emerged from basic science and pre-clinical animal models helping to better define the common biologic, genetic, and molecular make-up of these tumors. These data have not only provided a better understanding of tumor biology, but they have also provided new areas of research targeting molecular and genetic pathways with the potential for novel treatment strategies and improved patient outcomes. Here we provide a review of pediatric non-brainstem HGG, including epidemiology, presentation, histology, imaging characteristics, treatments, survival outcomes, and an overview of both basic and translational research. An understanding of all relevant pre-clinical tumor models, including their strengths and pitfalls is essential in realizing improved patient outcomes in this population.
Frontiers in Oncology 08/2012; 2:105. DOI:10.3389/fonc.2012.00105
"However, if the O6meG is not repaired before the re-synthesis step, it is believed that the repetitive cycle of futile MMR will generate tertiary lesions, most likely DSBs, eliciting a cell death response (Branch et al., 1993). Whereas a significant percentage of gliomas lack expression of MGMT, due to hypermethylation of the MGMT promoter, whereas at least half of glioblastomas multiforme (GBM) express MGMT, its expression being associated with resistance to chemotherapy and poor prognosis (Hegi et al., 2005; Pollack et al., 2006). Strategies to target the MMR pathway and to improve the efficacy of TMZ to overcome resistance resulting from MGMT activity have been implemented. "
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