Combining drugs necessary to suppress malignant childhood brain tumors
Researchers at IGP have together with American colleagues identified a weakness in the most serious types of malignant brain tumours in children. By using a combination of two different drugs they could inhibit both the cell cycle and the enhancer system in the cell, which was necessary to efficiently kill the brain tumour cells. The results have been published in the scientific journal Oncogene.
MYC is a protein that controls the activity of several other important genes by binding to specific sites in the genome (the DNA) in the nucleus of the cell. MYC proteins are elevated in aggressive types of cancer, including medulloblastoma, the most common type of malignant brain tumour in children. MYC proteins regulate the growth of the cell by instructing other proteins involved in cell cycle control to increase cell proliferation. MYC can also amplify the enhancer function of other cancer genes, which will make the cancer even more malignant. Despite the fact that MYC proteins are involved in almost half of all types of human cancer there are currently no efficient drugs that can suppress MYC proteins directly.
The research group first tested a drug that can suppress the protein CDK2 that controls the cell cycle of dividing cells. The drug was found to efficiently slow down the cell cycle but it could also suppress MYC itself in brain tumour cells. However, only in combination with a so called BET inhibitor, a substance that could block the function of MYC as an enhancer other cancer genes, the efficacy was good enough to block the growth of the cancer. Both substances were tested in various model systems driven by MYC proteins and in brain tumour cells from patients with elevated levels of MYC proteins.
“We found that the substances used in combination passed the blood-brain barrier, which suggests that they will actually reach the tumour and can attack the tumour cells in the brain. The blood-brain barrier surrounds our brain and normally acts very effectively to protect the brain from most substances, including several types of drugs. The fact that a drug reaches all the way to its target in the brain is of course a necessity in order to be effective in clinical treatment in these patients,” says Fredrik Swartling, Associate Professor at IGP, who has led the research study.
Only the drug that inhibits CDK2 is approved for clinical trials on other types of cancer. The BET inhibitor does not have the right stability and characteristics needed to be used clinically. In the absence of a more stable BET inhibitor that further can pass the blood-brain barrier it is not possible to use this combination on patients with medulloblastoma. Still, the results demonstrate that this combination of drugs can very effectively target the most aggressive types of childhood brain tumours that have elevated levels of MYC.