Researchers in Kumar Somasundaram’s laboratory at the Indian Institute of Science in Bangalore have a single-minded focus. The target of their attention is the glioblastoma – the most prevalent, stubborn and aggressive form of brain cancer. Somasundaram and his students have been carefully decoding the biology of the cancer to understand its many genetic triggers and protein pathways. The group’s recent breakthrough may indeed hold clues to treating glioblastomas.
Glioblastoma multiforme is cancer that arises out of astrocytes, which are one of many glial cells that form supporting structures for neurons in the brain. These transformed astrocytes grow quickly and invade healthy parts of the brain, making them difficult to resect (surgically cut out). Chemotherapy is also less effective for this form of cancer because the unique blood-brain barrier that allows only certain molecules into brain tissue keep drugs away from target tumors. In effect, glioblastoma patients have a median survival rate of between 15 and 17 months, which means that only half the number of patients diagnosed with such tumors live beyond one-and-a-half years from their diagnosis.
The perverse nature of the glioblastoma has forced medical researchers around the world to get really innovative while developing treatments. At Duke University in the United States, scientists are trying to use the modified polio virus to deliver drugs to tumor sites, with mixed results. Scientists at the University of Portsmouth recently announced a potential breakthrough by using reformulated soluble asprin and other ingredients, also to enable targeted drug delivery to the tumor.
Tale of two proteins
Somasundaram’s laboratory, working in collaboration with the National Institute of Mental Health and Neurosciences and Sri Sathya Sai Institutes of Higher Medical Sciences, is looking beyond crossing the blood-brain barrier. Their solution lies in decoding and suppressing protein pathways that allow the tumor to grow and spread. In two recent paper’s published in the Nature group’s journals Oncogene and Scientific Reports the group has detailed the functioning of two kinds of proteins – fibromodulin and CBx7.
Unlike other cancers, like breast cancer and lung cancer, that metastasize to other parts of the body through lymph circulation or blood circulation, glioblastomas do not go spread outside the brain. The tumor cells are, however, not restricted to the tumor area and can infiltrate other parts of the brain. Fibromodulin is produced by expression of the FMOD gene found in glioblastoma cell DNA and its presence causes tumor cells to migrate faster and farther.
“Patients who show higher fibromodulin levels will have more migratory tumor cells and therefore more aggressive tumors and may not respond to treatment well while patients will lower fibromodulin levels will have less aggressive tumors and will respond to treatment better,” said Somasundaram.
But while fibromodulin increases migration, the protein CBx7 actually inhibits migration. In a glioblastoma, the gene for CBx7 is silenced by methylation of its receptor so that it is not transcribed and the protein is not produces. Thus fibromudulin and CBx7 have opposite functions.
Decoding how tumors grow
Another angle that the researchers are using to approach the glioblastoma problem is to look at the tumor’s support structures. Tumors are made up of cancer stem cells and bulk cells. The bulk cells form the lion’s share of the tumor but the small number of stem cells retain the power to either form new stem cells from which new tumors can grow or to differentiate into bulk cells.
Tumors have lymphocytes and blood cells. Lymphocytes are cells of the immune system that come to the tumor area to kill the tumor. But a persistent tumor is able to overcome lymphocytes by secreting certain proteins, after which the lymphocytes help the tumor grow. Tumor cells also secrete endothelial growth factors that attract blood capillaries to the tumor and provide it nourishment.
Last year, researchers from Somasundaram’s lab published their study that showed the mechanism by which secretions from glioblastoma’s regulated the insulin-like growth factor-binding protein – IGFBP1 – that induced the growth of blood vessels in the tumor. Silencing this mechanism could inhibit the tumor’s growth.
Multi-pronged attack
Putting all these findings together, Somasundaram and his colleagues are devising ways to characterise glioblastomas and their different signatures.
“Why are some patients are responding better and some are not?” Somasundaram asked. “One hypothesis is that the information is in the tumor – that one tumor is resistant to treatment and another is not. We can look at the tumors an identify their signatures. We look at the signatures in each tumor and assign a score.” The score indicated whether a tumor is high-risk or low-risk.
Some tumors might have a particular pathway that is highly activated that makes the tumor aggressive, Somasundaram explained. If along with conventional treatment, doctors are able to deliver drugs that inhibit these protein pathways in high-risk tumors, they may be able to convert them into low-risk tumors that give their patients a better chance of living longer.
