Glioblastoma is the most aggressive brain tumor and, even with the current multimodal therapy, is an invariably lethal cancer with a life expectancy that depends on the tumor subtype but, even in the most favorable cases, rarely exceeds 2 years. Epigenetic factors play an important role in gliomagenesis, are strong predictors of outcome, and are important determinants for the resistance to radio- and chemotherapy. The latest addition to the epigenetic machinery is the noncoding RNA (ncRNA), that is, RNA molecules that are not translated into a protein and that exert their function by base pairing with other nucleic acids in a reversible and nonmutational mode. MicroRNAs (miRNA) are a class of ncRNA of about 22 bp that regulate gene expression by binding to complementary sequences in the mRNA and silence its translation into proteins. MicroRNAs reversibly regulate transcription through nonmutational mechanisms; accordingly, they can be considered as epigenetic effectors. In this review, we will discuss the role of miRNA in glioma focusing on their role in drug resistance and on their potential applications in the therapy of this tumor.

Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells

Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse intrinsic pontine glioma (DIPG). Synthetic inhibitors of KDM5A (JIB 04 and CPI-455) efficiently block the proliferation of native and TMZ-resistant cells and the KDM6B inhibitor GSK J4 improves survival in a model of DIPG. The aim of our work was to determine if GSK J4 could be effective against GB cells that have acquired TMZ resistance and if it could synergize with TMZ or JIB 04 to increase the clinical utility of these molecules. Standard functional and pharmacological analytical procedures were utilized to determine the efficacy of the molecules under study when used alone or in combination against native GB cells and in a model of drug resistance. The results of this study indicated that although GSK J4 is active against native and TMZ-resistant cells, it does so at a lower efficacy than JIB 04. Drug combination studies revealed that GSK J4, differently from JIB 04, does not synergize with TMZ. Interestingly, GSK J4 and JIB 04 strongly synergize and are a potent combination against TMZ-resistant cells. Further studies in animal models will be necessary to determine if this combination of molecules might foster the development of novel therapeutic approaches for glioblastoma.

In 1940, it was demonstrated that free DNA could be identified in the bloodstream. It was later shown that circulating nucleic acids (CNA), both DNA and RNA, are present in several neoplastic and non-neoplastic diseases, and that in cancer they originate mostly from the tumor. In this review, we discuss the potential application of CNA as a breast cancer biomarker for early diagnosis and patient evaluation. Most of the initial studies on CNA compared the levels of CNA in cancer patients and healthy individuals. To increase sensitivity and specificity, cancer-specific molecular alterations were then utilized. In this respect, epigenetic alterations and micro-RNA offer considerable advantages over mutations because of their easiness of detection. Epigenetic signatures, being early events of carcinogenesis, may also be valuable markers for screening purposes. Monitoring the follow-up of the patients is one of the most interesting applications of CNA-based assays, and it is reasonable to hypothesize that CNA may become a surrogate marker for circulating cancer cells in the prediction of patient outcome. Transferring these findings to the clinical practice is the next effort, and this will be possible when a ‘common language’ is defined to allow proper validation of these new markers.