Glioblastoma multiforme- the most aggressive form of brain tumor
There are many types of brain tumors, which can arise in the cells of the brain or the surrounding tissues. Glioblastoma multiforme (GBM) (also called glioblastoma) is a fast-growing and highly invasive type of glioma that develops from star-shaped glial cells (astrocytes and oligodendrocytes) which support the health of the nerve cells within the brain. GBM is the most common malignant primary brain tumor making up 54% of all gliomas and 16% of all primary brain tumors. Treatment of GBM is complex due to the following reasons:
+ Localization of tumors in the brain make safe surgical resection difficult
+ Inherent resistance of the cancer cells to conventional therapy
+ Limited capacity of the brain to repair itself
+ Potential of malignant cells to spread into nearby brain tissue
+ Tumor heterogeneity (tumor contains many different types of cells)
+ The brains’ natural protective barrier (blood-brain barrier, BBB) inhibits effective drug delivery
+ Harmful side effects associated with the treatments
Despite technological advances in the standard treatment, including surgery and radio-chemotherapy, GBM remains incurable with a median survival of only 15 months. Thus, there is an urgent need to develop next generation therapeutic approaches with the aim to improve survival for patients with this deadly disease.
miR-7 and GBM
In attempts to uncover the molecular drivers of GBM, the epidermal growth factor receptor (EGFR) has been found to be genetically altered in 50-60% of GBMs. The EGFR sends downstream signals, through the phosphatidylinositol 3-kinase (PI3K)/Akt and the ras-raf-mitogen-activated protein kinase (MAPK) pathways (among others), prompting the cancer cells to grow, survive and spread uncontrollably. Accordingly, strategies have been developed to target the EGFR pathway including tyrosine kinase inhibitors (TKIs), monoclonal antibodies and RNA-based agents. We have found that a microRNA (miRNA), known as miR-7 is an effective RNA-based agent capable of inhibiting EGFR in GBM (full article). miR-7 specifically targets several regions of EGFR messenger RNA (mRNA) promoting its breakdown and stopping it from being made into the functional protein. We also observed that the expression of miR-7 was significantly down-regulated in EGFR-positive GBM cells compared with RNA extracted from total normal human brain tissue, consistent with “loss of the brake on EGFR” with the development of GBM. Our in vivo studies have confirmed that miR-7 is a potent suppressor of intracerebral tumors and significantly prolonged the survival of mice. miReven aims to progress mRx-7 (a modified miR-7 mimic) along the oncogenic pipeline towards a targeted delivery mechanism to improve the survival outcomes of patients with GBM.