Worldwide Cancer Research Menu

Testing TRRAP as a treatment for malignant brain tumours

Brain tumours, in particular a type called Glioblastoma, can spread quickly through the brain. This makes it a difficult cancer to treat. One major advance in the research of brain cancer was the identification of brain tumour stem cells (BTSCs). Stem cells are a kind of "starter cell", which can multiply and change into a wide variety of other cell types, depending on where they are located in the body. It is thought that these BTSCs are the most dangerous type of cell within brain tumours. BTSCs are able to "renew" themselves, and are therefore able to avoid being killed by anti-tumour treatments. Scientists want to try to develop drugs that stop the BTSCs from growing and spreading within the brain.

Dr Wurdak previously found that a protein called TRRAP was directly involved in making BTSCs grow. There is also evidence that brain tumour patients that have TRRAP in their tumours may be less likely to survive the disease. There are currently no treatments that stop TRRAP from working because there are many molecules related to the protein, and scientists donUt yet fully understand exactly how TRRAP works with the BTSCs.

Dr Wurdak and his team will use the Worldwide Cancer Research grant to study how TRRAP works and which parts of the protein are responsible for making the BTSCs grow. They want to find out whether removing TRRAP at the time when the brain tumour is spreading to other parts of the brain can stop the spread of the disease. They also hope to test whether blocking TRRAP might be a way to enhance the effects of chemotherapy. They hope that their research will ultimately allow drugs to be developed against TRRAP, leading to new treatments for incurable types of brain cancer.

Gene tagging and its role in glioma recurrence

Thousands of genes within our cells act as our blueprint, by controlling our cells' behaviour. The way that these genes work can sometimes be controlled by adding specific chemical groups or "tags" on to the genes, or the proteins that act as their scaffolding. The addition of these tags can lead to an increase or decrease in the activity of genes, and adding the tags in different patterns, in different places, leads to different effects. This often happens incorrectly in cancers, when incorrect changes in gene activity can allow the cell to grow and divide in an uncontrolled manner, forming a tumour. One such form of tagging is called DNA methylation, where the tag is a small molecule called a methyl group. Addition of too many of these methyl groups to genes is linked with tumour development.

Dr Testa will be continuing the research from a previous Worldwide Cancer Research grant where he has been investigating how methylation of histone H3, a gene scaffolding protein, is involved in the development of glioma. Gliomas are the most common type of brain tumour, and they are made up of a group of 3 different types of brain tumours, which includes glioblastoma multiforme (GBM).

Dr Testa and his team found a window of time during GBM development, in which tumour growth was dependent on a specific pattern of methylation on histone H3. They want to continue this work with their new grant, by studying how these gene tags are involved in gliomas recurring. They will be using tissue samples from GBM patients. Surgery is becoming less frequent when GBM recurs, so these samples are a unique opportunity to study the relationship between gene tagging and the development of the disease. They will use an innovative combination of computer analysis and lab experiments to study gene networks involved in this disease. This research will hopefully give us a better understanding of how gene tagging affects different stages of the disease.

The MYCN protein and its involvement in brain tumours

Medulloblastoma is one of the most common malignant brain tumours in children. Malignant tumours are different from benign tumours as they will expand and spread to surrounding areas of the brain, causing damage. A protein called MYCN is needed for normal brain development, but in medulloblastoma too much MYCN can be present.

Dr Swartling and his team have created two different types of genetically modified mice, which allow them to study brain tumours caused by MYCN. They have discovered that one of the reasons that MYCN can accumulate in brain tumours is because it is not being broken down the way it should be. A system known as the ubiquitin system is responsible for breaking down MYCN in healthy brain cells, but in some medulloblastomas this system does not work properly. A molecule called FBW7 works on MYCN and is part of the ubiquitin system, but seems to be mutated in medulloblastoma, or there is much less of the molecule in cancer cells.

With their new grant, they want to study, in detail, the importance of FBW7 and MYCN in the development and growth of brain tumours. They hope to find what causes MYCN-driven brain cancer, and to find new ways to control stabilisation of this protein.

Understanding the role of stem cells in tumours of the brain and pituitary gland

All normal tissues within our bodies have a tiny population of stem cells. These are amazing 'starter cells' which have the unique ability to multiply and change into a variety of other cells depending on the tissue in which they are located in the body. The worrying discovery of a small group of cancer cells with stem cell properties, known as cancer stem cells, in several different types of cancer has profound implications for cancer treatments. It is thought that these cancer stem cells could be responsible for the progression, spread and reoccurrence of cancers as they seem to be able to escape death when treated with anti-cancer drugs.

Some cancer stem cells are thought to originate from tissue stem cells and it is therefore important for scientists to identify and understand the differences between these 'good' tissue stem cells which can be helpful in regenerative medicine and 'bad' cancer stem cells which need to be killed. Dr Lovell-Badge has identified two proteins called SOX2 and p27 which he thinks are involved in normal stem cells and which, when altered, have a detrimental role in creating cancer stem cells. Dr Lovell-Badge is therefore using his Worldwide Cancer Research grant to investigate the part played by SOX2 and p27 in the development of brain tumours called glioblastomas and in pituitary adenomas.

Could a patient’s body clock help beat brain tumors?

Circadian rhythms or ‘body clocks’ are present in nearly all cells of animals and humans.  They help us adapt to the predictable daily change in light, temperature and environmental conditions.

Dr Satchidananda Panda explains “A prolonged disruption of our body clock – for example in shift work – has recently been confirmed as a novel cancer risk factor by the WHO International Agency for Research on Cancer (IARC). Body clock genes regulate several basic functions of the cells, including energy usage, interaction with their environment, the way they respond to DNA damage and cell division; these processes are also disrupted in cancer. Therefore, altering the body clock genes could be a novel way to kill the cancer cells. However, this concept has never been exploited for the generation of new anticancer therapies.”

He continued “We want to test this hypothesis as a novel treatment option for the most aggressive brain cancer: glioblastoma multiforme (GBM). GBM has poor survival rates, it develops resistance to current treatments and often reoccurs.  Previous studies indicate that GBM stem cells are one way the cancer returns and so are a crucial target for the generation of new treatments.

GBM stem cells show disruption of circadian rhythms, yet expression of some of the clock genes continue. We recently observed that interrupting clock genes with drugs can trigger a cascade of gene expression changes leading to cell death only in GBM stem cells and sparing the normal cells.

The GBM stem cells are also more sensitive to these clock drugs than the current drugs on the market. In order to verify the use of these drugs as a novel therapy for GBM we propose exploring the efficiency in patient-derived glioblastoma tissue samples alone or in combination with other standard drugs on the market. This study may provide a previously unknown therapeutic strategy for GBM treatment and open the road for a novel class of drugs.”