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Towards a better therapy for brain cancer

Glioblastoma (GBM) is a type of cancer in brain cells. The brain mostly consists of two cell types, neurons which transmit information through electric impulses and glia which support the neurons and maintain their health. Cancer of the glia is called as glioma. GBM (grade IV) is the most common and most aggressive type of glioma. It accounts for 15% of all brain tumors and 50% of all the gliomas. It is most common between age group of 45-65 years and men get affected more than women. Among children, GBM is the second most prevalent cancer. At present, the standard treatment for GBM is surgery followed by radiation along with chemotherapy. Despite the current treatment options, GBM has very poor prognosis with a median survival of 15 months after diagnosis. Almost all cases of GBM show recurrence and this can be attributed to various factors like incomplete resection, genetic variations among tumors, invading tumor cells, and the presence of cancer stem cells.

Prognosis of a disease means prediction of the outcome after the disease is diagnosed. To date, there are only few prognostic markers for GBM that are translated to clinics with limited utility like mutation of IDH1 gene and methylation of the MGMT gene. Hence, a need for robust prognostic signatures (multiple genes) that can identify the disease outcome and also guide clinicians in giving appropriate treatment to the patients is becoming more and more essential. By using prognostic signatures, it is now possible to identify GBM patients with low risk who respond to the current treatment with the maximum benefit. It is also possible to identify patients with high risk who do not respond to the current treatment, in which case possible alternative and aggressive treatment could be tried. Targeted therapy involves identification of molecular changes in an individual’s tumor cells and targeting those altered molecules by specific inhibitors. Although various such altered molecules have been identified in GBM scenario, targeting those molecules have been proven to be futile. Hence, another important aspect in glioma biology that scientists need to address is identification of novel targets for GBM treatment.

At Indian Institute of Science, the laboratory of Prof. Kumar Somasundaram, in collaboration with groups from National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore led by Dr. Vani Santosh, Dr. A Arivazhagan and other investigators and Sri Sathya Sai Institute of Higher Medical Sciences (SSSIHMS) led by Dr. AS Hegde in Bangalore is exploring the biology behind GBM. Recent discoveries from the group could pave the path to better therapeutic options for GBM. Current diagnostics for GBM includes MR imaging (MRI) and histopathological investigation of the tumor tissue. However, these techniques fall short in predicting the true tumor boundary, the aggressiveness of the tumor and responsiveness of patients to therapy etc. Therefore, it is imperative to find better prognostic and diagnostic parameters that can identify GBM patients as well as their risk status. The laboratory at IISc has identified various diagnostic and prognostic signatures through multiple studies. This could be helpful in providing patient specific treatment and thus could increase the chance of survival.

During GBM development from normal glial cells, there would be changes in the level of expression of different genes/proteins. If a set of genes show consistent increase or decrease in the expression level, it could be used as a marker for the disease condition. A modification of the genome, wherein specific genes are methylated in disease condition can also serve as a signature for the disease. To study the gene expression and various other molecular changes, tumor samples are collected during the surgery and serum is collected before and after the surgery of patients.

Prof. Somasundaram’s group has identified various diagnostic signatures like a gene expression signature from tumor tissue samples that can distinguish  GBM from grade III glioma. They have come up with a set of markers which are secreted in the serum of the patient which can differentiate GBM patients from normal individuals. To find out a specific set of serum protein markers for GBM, the serum sample from the patients before surgery were checked for the proteins which were then compared to the serum of normal individuals. They have identified a three-marker panel which includes LYAM1, BHE40and CRP proteins, which can discriminate between GBM sera from that of a healthy individual. However, further experiments need to be carried out to see if this signature can differentiate GBM patients from patients with other brain-related disorders. Only then it can be used as a robust diagnostic signature for GBM patients. Additionally, various prognostic signatures have also been developed that can identify the risk status of GBM patients. For example, a DNA methylation signature of a set of 9 genes has been identified as a prognostic marker. This study also revealed that the patients classified as high risk by the above 9-gene methylation signature have high activation of an oncogenic pathway. Inhibitor against the central molecule of the above pathway may be considered as a potential therapeutic option for this group of patients. Thus, this is an example of how patients can be stratified according to their risk and hence most appropriate therapy could be chosen.

In the past many decades, efforts have been undertaken to find out key genetic alterations in various cancers including GBM which paved ways to develop targeted therapies. In fact, other groups have identified a particular molecule called VEGF which plays a major role in angiogenesis or development of new blood vessels in the tumor to be highly upregulated in GBM. Efforts were put together to target this molecule and an inhibitor of VEGF, Bevacizumab (Roche Inc), was tested for its efficacy in GBM targeted therapy. However, such studies showed Bevacizumab failed to provide any survival benefit to GBM patients. The failure was attributed to the fact that other angiogenesis inducing molecules secreted by the tumor may be responsible for tumor cell sustenance. In one study from Prof. Somasundaram’s lab, they have identified IGFBP1 which is secreted by non-tumor cells present within the tumor as a potential target for GBM therapy. Basically, the non-tumor cells which form the tumor micro-environment secrete multiple factors that can help in tumor growth and maintenance. These molecules need to be translated to the clinics as potential targeted therapeutic options. With an increasing list of various diagnostic/prognostic markers and potential targets for GBM treatment from Prof. Somasundaram’s research group, we are going towards a better future for GBM patients.

 

Kumar Somasundaram is a Professor in the Department of Microbiology and Cell Biology, Indian Institute of Science. He can be reached at +91 80 23607171. 

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