“Our findings show that inhibiting PRMT5 can affect both mature and immature tumour cells in glioblastoma,” said chief researcher Balveen Kaur, Ph.D. PRMT5 has been known to function solely in the regulation of gene expression, but the study has recently discovered that its expression is positively associated with malignancy and negatively with patient survival.
Glioblastoma: the most malignant form of brain cancerGlioblastomas are tumours that come from astrocytes, which are the glial or star-shaped cells that go into making the supportive tissue structure of the brain. They are the most aggressive and malignant form of brain cancer and made up about 15 per cent of all brain cancers diagnosed. Around one out of five brain tumours are glioblastomas. Chances of developing brain cancer increase with age, and current data indicates that men are more susceptible to this form of brain cancer than women.
Brain cancers are rare compared other more prominent types of cancer in Singapore. According to National Cancer Centre Singapore, about 1,903 cases of brain cancer were reported between 1968 and 2007, while National Neurological Institute reported an annual rate of 50 new cases of glioblastoma muliforme (GBM). However, Singapore is actively involved in ongoing research efforts, such as the discovery of a powerful way to classify patients with glioblastoma by local scientists.
Glioblastoma comprises of malignant, grade 4 tumours which are initially found in the cerebrum, the biggest and uppermost region of the brain responsible for language as well as visual and spatial information processing. Most patients with the condition notice pressure in the area and experience headaches, vision changes, seizures, mood swings, and sudden speech impediments.
Many patients with aggressive forms of the cancer do not live longer than a year. Treatment is difficult due to tumour cells’ resistance to regular cancer treatments. Furthermore, the human brain is highly vulnerable to damage and does not easily heal as compared to others. Many of the drugs used in cancer treatments are also unable to penetrate the blood-brain barrier to reach the cancerous tumours within and take effect on them.
Drug should target both immature and mature cancer cellsGlioblastoma cancer cells have mature and immature forms. As a result, even if one cluster of cancer cells was eradicated by a drug, the other cluster continues to thrive. Since glioblastoma tumours are highly metastatic and invasive, they are able to resist therapies such as radiation treatment and surgery. Research on the tumours should therefore focus on developing a drug that could target both populations of mature and immature cells.
The team led by Dr Balveen Kaur utilized cell cultures from both types of glioblastoma cells and proceeded to remove PRMT5 with RNA silencing process. Using mice to study the effects of inhibiting PRMT5, the researchers infected the animals with glioblastomas comprised entirely of only either immature or mature cells. The findings revealed that the mice showed decreased tumour sizes and growth rates. More mice managed to survive as well.
The researchers found that the enzyme is needed by both immature and mature glioblastoma cells, with differences in PRMT5 mechanisms in each group. Immature cancer cells need the enzyme for a proper cell cycle, and when it is removed, the researchers found that the cells stopped splitting, leading to stunted growth of the tumour. In the case of mature cancer cells, the removal of the enzyme caused cell death by apoptosis.
The findings have revealed the need to target glioblastoma at the molecular level. A drug which can inhibit the relationship between the immature and mature cells would therefore lead to the inability of the cancer to grow or develop resistance to treatment. The breakthrough research points to the potential of developing PRMT5 inhibitor drugs in the fight against brain cancers caused by glioblastoma tumours. MIMS
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Targeted cancer therapy