A new approach to treat glioblastoma multiforme and its recurrences
Results of a study by a group of researchers from IRCCS Ospedale San Raffaele and the Institute of Neuroscience of the National Research Council of Milan (CNR-In), coordinated by Vania Broccoli and Alessandro Sessa, are published in the scientific journal Science Advances. The article describes a new therapeutic approach for the treatment of brain tumors, particularly glioblastoma multiforme (GBM) and its recurrences.
By studying cancer cells and cancer stem cells in culture, researchers developed novel anticancer factors that can inactivate and silence particular pro-tumor factors. This action occurs specifically and exclusively in brain cancer cells, thus preventing tumor growth and recurrence. The treatment has been shown to be as effective in tumor cells as it is inert, and therefore safe, in healthy ones, such as neurons.
The research, carried out in vitro and in vivo in experimental models of glioblastoma, was supported by AIRC Foundation for Cancer Research and MUR, and paves the way for the development of potential new therapies for this and other tumor types.
The problem of recurrence in glioblastoma multiforme
Glioblastoma multiforme is a very aggressive form of brain tumor that is still difficult to treat, partly because of its numerous recurrences. GBM patients usually undergo surgery to remove the tumor, which is followed by radiotherapy and chemotherapy. Despite this, it is difficult to prevent tumor recurrence in almost all cases. This is because the few cancer cells that remain dormant in healthy tissue after treatments are able to develop resistance to treatments.
"With the goal of achieving long-lasting remission for this type of tumor, we have been engaged in the laboratory for years in developing an effective strategy to target both residual diseased cells and cancer stem cells, and suppress their tumor activity," says Vania Broccoli, head of Stem Cells and Neurogenesis Unit at San Raffaele Hospital and CNR-In.
New therapeutic approach developed at San Raffaele
Cancer stem cells, often quiescent but capable of self-renewal and tumor reform, use particular proteins called 'transcription factors' to grow and proliferate. Among them, the SOX2 protein is produced from an oncogene found in most brain tumors, of which it promotes their development and aggressiveness.
In the laboratory, researchers blocked the oncogenic activity of SOX2, creating a faithful copy of it, but with opposite function and thus capable of inhibiting all its target genes. Thus, this genetic 'avatar' is capable of disabling the entire genetic network downstream of the SOX2 oncogene.
"Our idea was to inactivate the SOX2 oncogene, which normally sustains tumor malignancy, through the creation of an antithetical copy, thus developing a true anti-tumor factor. To do this, we used a gene therapy technique by inserting the new anti-tumor factor, called SOX2 Epigenetic Silencer (SES), into viral vectors, inoculated directly at the targeted site. We were thus able to eliminate or dramatically reduce tumor growth in models of GBM both in vitro and in vivo," says Alessandro Sessa.
"The treatment has been shown to be effective and specific for cancer cells and cancer stem cells. We have also been able to see its safety as it does not damage other healthy cells in the brain tissue, such as neurons or glia."
The results obtained will now need to be confirmed in further preclinical studies before they can be evaluated in clinical trials with patients. "We hope that this new approach may soon complement current therapies for GBM. The treatment could be carried out at the same time as surgical removal, without the need to suspend chemiotherapy and radiotherapy, today the standard for this type of tumor," concludes Vania Broccoli.
The results of this study could also be applied to the treatment of other types of cancer. SOX2 is indeed present in several tumor types and in some liver metastases. Moreover, the technique developed is modulable and versatile and could be used, in principle, to deliver other anticancer factors, with applications against lung, breast, liver, or kidney cancers