CNIO researchers studied the resistance to temozolomide, the first-line treatment for glioblastoma, and over time, many patients no longer respond to the drug. The combination of the drug and dianhydrogalactitol has a synergistic effect, which can circumvent these resistances and increase the survival rate of mice with brain tumors.
This Glioblastoma Yes Brain tumor More often and more aggressively. In the past 50 years, their survival rates have hardly increased, which highlights the urgent need to develop new treatment strategies. Now, the National Cancer Research Center (CNIO) A treatment strategy based on a combination of the following factors is proposed Sclerotidae, The first-line treatment of these patients, and Disaccharide galactose, The drug is in clinical trials and has been approved for the treatment of other tumors.
Currently, the main and almost only treatment for glioblastoma is to combine radiotherapy with a chemotherapeutic agent called temozolomide after surgical removal of the tumor mass. Like most chemotherapy treatments, temozolomide induces damage to the genetic material of tumor cells, which can lead to tumor collapse and cell death. However, in almost half of patients, these types of tumors are resistant to the drug, and even under treatment, the tumors continue to grow.
Although the incidence of glioblastomas is not very high in adults, they are the most common brain tumors, and there are no effective treatments or markers of response to treatment or development of drug resistance.
He said: “Although the incidence of adult glioblastomas is not very high, they are the most common brain tumors. There are no effective treatments or markers of response to treatment or drug resistance. Massimo SquatritoHead of the brain tumor team of the Seve-Ballesteros Foundation.The work has been published in the magazine this week Molecular Cancer Therapeutics.
DNA repair, the origin of drug resistance
To answer the question of why patients with glioblastoma stopped responding to temozolomide, Squatricos and his team observed that certain glioblastomas cause genomic rearrangements of DNA repair genes. MGMTIt increases production, repairs the DNA damage caused by temozolomide, and tumors can grow and avoid treatment.These results were published last year Nature Communications.
In the current work, the researchers studied the resistance to temozolomide in depth, for which they used glioblastoma cell lines, which have different key genes that are silenced. The data highlights that these resistances not only depend on the MGMT gene, but may also be mediated by the failure of the MMR (DNA repair) pathway. Therefore, when any of its components are changed, tumor cells will accumulate mutations, thereby conferring resistance on them. Cancer ability. Avoid the effects of temozolomide.
Tumors are complex systems that deploy multiple tools to trick the human body into growth and development. Experts believe that for many patients, one of the great revolutions and hopes is the combination therapy for these multiple components that interfere with the tumor process: combine them in a targeted way to combat them and avoid the resistance they produce “.
Better combination therapy
Researchers focused on the drug dihydrogalactoside, a chemotherapy that can cross the blood-brain barrier and reach the central nervous system, where it induces DNA damage in tumor cells. Currently, the drug is being tested in clinical trials for glioma and other types of cancer (such as ovarian cancer), and has been approved in China for the treatment of acute myeloid leukemia and lung cancer.
The results show that the combination of temozolomide and dianhydrogalactitol has a synergistic effect. in vitro Therefore, the growth of these cells was observed to be lower compared to when these drugs were used alone. The authors have described that similar results were obtained in mice with brain tumors, which survived longer when treated with temozolomide and dihydrogalactitol at the same time.
In addition, the results obtained indicate that, unlike temozolomide, the anti-cancer effect of dihydrogalactitol is independent of the MGMT DNA repair gene and the MMR pathway. He explained: “Our data suggests that dianhydrogalactitol may be an effective treatment that can bypass the resistance mechanism that appears in temozolomide therapy.” Miguel Jiménez Alcazar, The first signatory of the article.
Squa recently stated: “This is very interesting because it may lead to a substantial improvement in the evolution of these patients.” “There is an urgent need to incorporate these studies into clinical practice to see if this combination of drugs can improve survival. He concluded: “Both drugs are available clinically, which may speed up the development time of this new method. “
Miguel Jiménez-Alcázar, Álvaro Curiel-García, Paula Nogales, Javier Perales-Patón, Alberto J. Schuhmacher, Marcos Galán-Ganga, Lucía Zhu, Scott W. Lowe, Fátima Al-Shahrour, Massimo Squa. “Dihydrogalactitol overcomes multiple temozolomide resistance mechanisms of glioblastoma.” Molecular Cancer Therapeutics, 2021. DOI: 10.1158 / 1535-7163. MCT-20-0319
This research was funded by the Ministry of Science and Innovation, the Carlos III Health Institute, the Sev Ballestros Foundation, the Spanish Anti-Cancer Association (AECC) and the European Molecular Biology Organization (EMBO).