ABSTRACT
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response (AU9
No disponible
Subject(s)
Humans , Male , Female , Glioblastoma/diagnosis , Glioblastoma/radiotherapy , PTEN Phosphohydrolase/administration & dosage , PTEN Phosphohydrolase/analysis , Biomarkers/analysis , Biomarkers, Tumor/analysis , Chemoradiotherapy, Adjuvant/methods , PTEN Phosphohydrolase/radiation effects , Radiation Tolerance/radiation effects , Phosphatidylinositol 4,5-Diphosphate/analysis , Phosphatidylinositol 4,5-Diphosphate/radiation effects , Adenosine Diphosphate Ribose/analysis , Adenosine Diphosphate Ribose/radiation effectsABSTRACT
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.
Subject(s)
Brain Neoplasms/genetics , Chemoradiotherapy , Glioblastoma/genetics , Mutation/genetics , PTEN Phosphohydrolase/genetics , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Biomarkers, Tumor/genetics , Brain Neoplasms/therapy , Glioblastoma/therapy , Humans , PrognosisABSTRACT
Clinical studies in patients with newly diagnosed glioblastoma treated with temozolomide have shown that the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is both predictive and prognostic of outcome. Methylation of the promoter region of MGMT is the most clinically relevant measure of MGMT expression and its assessment has become integral in current and planned clinical trials in glioblastoma. Our study confirmed that MGMT methylation, assessed by pyrosequencing, is associated with a significant survival benefit in glioblastoma patients treated with temozolomide (either concurrently with radiotherapy or sequential treatment). More interestingly, our study demonstrated that a promoter variant, the c.-56C>T (rs16906252) single nucleotide polymorphism (SNP) located within a cis-acting enhancer element at the proximal end of MGMT, is associated with the presence of MGMT promoter methylation in de novo glioblastoma. Furthermore, we show that the overall survival of patients carrying both the SNP and MGMT methylation showed a strong survival benefit when compared to either molecular event on their own. Promoter reporter experiments in MGMT methylated glioblastoma cell lines showed the T allele conferred a â¼30% reduction in normalised MGMT promoter activity compared to the wild-type haplotype. This might account for the propensity of the T allele to undergo promoter methylation, and in turn, the improved survival observed in carriers of the T allele. An independent validation on larger cohorts is required to confirm the prognostic and predictive value of individuals carrying the T allele.
