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New data on why the treatments against the most aggressive brain tumors fail found, which could be used for developing new therapies

A research team, with the participation of the University of Granada (UGR), has made some progress in determining the causes for glioblastoma multiforme (GBM), one of the most aggressive brain tumors known, to be resistant to the drugs currently used, which is one of the main limitations of its treatment. The results have been recently published in two articles in PLOS ONE magazine.

The researchers have proven that proteoglycans (the cells’ structural elements), called decorin (DCN) and lumican (LUM), could be decisive in the behavior and development of a resistance to the drugs used for treating glioblastoma multiforme, such as temozolamide (TMZ). In the other hand, they have laid bare that the inhibition of the transcription of some of the sub-units belonging to the mismatch-repair (MMR) complex, a system that analyzes and repairs DNA, could be responsible of the failure of current therapies against this kind of tumor.

This is a scientific breakthrough that could be useful for the search of new resistance markers in GBM as well as for the development of new therapeutic strategies which avoid the resistance to drugs that this tumors possess.

The researches on glioblastoma stem-like cells have been carried out by researchers from the UGR Institute of Biopathology and Regenerative Medicine (Instituto de BiopatologĂ­a y Medicina Regenerativa, IBIMER) and from the Biosanitary Institute of Granada (group CTS 107), in collaboration with the Bellvitge Biomedical Research Institute (Barcelona) and the Service of Medical Oncology (Granada) in the one hand, and the National Institute of Biostructures and Biosystems (Istituto Nazionale Biostrutture e Biosistemi, INBB, Rome) and the department of Biomedical Sciences (University of Sassari, Rome) in the other hand.

Low survival rate

GBMs, the most frequent and most aggressive tumors that affect the central nervous system, still present a low survival rate (less than a year and a half since its diagnosis), despite the use of TMZ combined with other drugs or with radiotherapy. This is due to, among other causes, the development of a resistance to the treatment.

This work analyzes how the massive, synergistic expression of DCN and LUM in neurospheres of stem-like cells derived from GBM is correlated with a lower tumor cells proliferation rate and with a lower development of apoptosis (a type of cellular death used by pluricellular organisms to eliminate damaged or unnecessary cells), but also its correlation with the rise in the resistance against TMZ treatments, which is one of the main drugs currently used in the treatment of this patients.

In the other hand, researches carried out in glioblastoma and neuroblastoma cell lines exposed to some drugs have proven that TMZ resistance is caused not only by the classic mechanism of the DNA-repairing enzyme MGMT, but it’s also related with the silencing of the MMR complex after the exposure to the drug.

The researches are now focused on proving the relevance of these two molecules in the ‘in vivo’ behavior of glioblastomas and analyzing the resistance mechanism based in the MMR complex.