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Targeting molecular blips on brain cancer chromosomes

DNA – the vital life molecule that contains the genetic code – exists in the nucleus of cells in tightly wound structures called chromosomes. The way the DNA is wound into chromosomes is precise and mistakes in the process are frequently associated with the onset of cancer. This is particularly true for gliomas, or brain tumours.

Dr Wong and her team at Monash University in Australia have worked out that a tiny alteration to chromosome structure can be used to identify tumour cells from normal cells. Using funding from Worldwide Cancer Research and The Brain Tumour Charity, Dr Wong now wants to investigate exactly how these changes drive tumour growth in conditions such as glioma. This work will ultimately identify weaknesses in these cancers that might be able to be hit with targeted treatments.

Beating treatment resistance in childhood brain cancers

Targeted cancer treatments can be very effective, but they don’t work the same for everyone because some patient’s tumours will inevitably develop resistance to the treatment, or be resistant already. Professor Adrian Bracken at Trinity College Dublin is using funding from Worldwide Cancer Research and The Brain Tumour Charity to look for ways to bypass resistance to a treatment for a rare but aggressive childhood brain cancer called paediatric diffuse intrinsic pontine gliomas (DIPG).

Proteins in cells that regulate the on/off state of genes have been implicated in a variety of cancers and recent breakthroughs have identified once such protein, called EZH2, as a promising target for treating DIPG.

It’s inevitable that some tumours will be resistant to drugs that block EZH2, so Professor Bracken is looking for ways to indirectly block it by targeting other associated proteins. Research has shown that EZH2 works in concert with several other proteins - so his team wants to find out if they can inhibit these to produce the same cancer-stopping effect.

Novel drugs targeting the cells circadian rhythm offer new hope for future treatment of brain cancer

A study in mice shows how a new experimental drug could be a highly targeted treatment for brain cancer. The research, co-funded by the charity Worldwide Cancer Research and published in the journal Nature, establishes a path forward for generating a novel class of drugs that could also be used for a wide range of other cancers.

The researchers show that the drugs effectively starve the cancer cells to death by attacking their ability to sustain the high metabolic demand they need for continuous growth and replication.

The drug molecules, which are able to cross the protective barrier around the brain, reduced the growth of brain tumours, called glioblastomas, and lengthened survival time of mice. Results at this stage are similar to what is expected with the current standard of care for glioblastoma but with no toxicity or side effects.

In laboratory tests, the drugs also demonstrated selective cancer killing ability against breast, colon, leukaemia, brain and melanoma cancer cells with no apparent effects on normal cells. This data suggests that these drugs are a novel pharmacological tool for targeting cancer cells with high selectivity and low toxicity, against possibly a wide spectrum of tumours.

The researchers, led by Dr Satchindananda Panda at the Salk Institute for Biological Studies in La Jolla, California, found that the drugs work by interfering with the circadian rhythm (the internal “clock”) of cancer cells. The drugs activate a molecular component of the cellular clock, called REV-ERBs, which causes the cells to die.

Dr Panda, an associate professor in the Salk Institute’s Regulatory Biology Laboratory and senior author of the new paper, said: “We’ve always thought about ways to stop cancer cells from dividing. But once they divide, they also have to grow before they can divide again, and to grow they need all these raw materials that are normally in short supply.”

“Targeting REV-ERBs seemed to work in all the types of cancer we tried. That makes sense because irrespective of where or how a cancer started, all cancer cells need more nutrients and more recycled materials to build new cells.”

The researchers found that cancer cell death was induced because activating REV-ERBs led to the cells being unable to cope with the high metabolic demand created by their constant drive to grow and divide. They also found that the drugs could kill pre-malignant cells – or cells which are not yet proliferating uncontrollably but act as the seed to kick-start tumour growth – suggesting that treatment could be effective at eradicating those hard-to-treat, dormant cancer cells.

Dr Helen Rippon, Chief Executive of Worldwide Cancer Research, said: “Cancer cells often seem to have a broken internal ‘clock’. Not only does this disrupt the cells’ daily rhythms, but can also turn on molecular circuits that drive tumour growth.”

“Understanding these underlying faults at the root of cancer is essential if we are to develop completely new treatments that are more effective and have fewer side effects.  We are delighted that this research is already leading towards new treatments for brain tumours and that early results suggest it could be a fruitful approach for other cancers too.”

Studying how ‘bubbles’ released by glioblastoma (brain) tumours enable them to grow and spread

Dr Kasper Rouschop is studying how 'bubbles' released by glioblastoma (brain) cancer cells encourage blood vessels to grow into the tumour.

Within tumors, areas exist that are exposed to very low levels of oxygen as it is used up by the rapidly growing cells. These are known as 'hypoxic regions' and they contribute to drug and radiotherapy resistance. They also allow the tumour to progress and grow by stimulating new blood vessel development which bring in food supplies, take away waste products, delivers new oxygen to relieve hypoxia and allow cancer cells to enter the blood stream and start secondary tumours elsewhere in the body, known as metastasis.

Dr Rouschop told us "In part, the hypoxic cells facilitate these effects. Recently we identified vesicles, small 'bubbles,' that are involved in the release of factors that promote blood vessel growth. Now we are trying to determine how these vesicles are created, pinpoint what their role is in tumor progression and identify their mechanism of action."

He concluded "We anticipate that the results of this research will enable us to evaluate whether targeting these particular bubbles could be a potential new way to reduce the growth of brain tumours. Our approach is highly innovative and is based on our previous identification of “bubbles” that are specifically released by hypoxic tumour cells. Without the support of Worldwide Cancer Research, evaluation of this promising approach would not be possible.”

Using fruit flies to study how brain tumours develop

Professor Christos Delidakis is studying how brain tumours develop, with the help of fruit flies. Contrary to common belief, insects can get cancer. In fact, with the right genetic tools researchers can create fruit fly tumours with particular defects that mimic those often found to be responsible for human cancers.

Professor Delidakis told us “We plan to use the fruit fly Drosophila to study a tumour model. The advantages of using flies are many – to name a few: easy, cheap and quick to grow in the lab, sophisticated yet exquisitely easy to use genetic tools, compact genome, great ease to isolate and image tissues under the microscope.”

He continued “When a molecular pathway called Notch is over-activated in fly brains, the brains grow to a larger size and consist of masses of cells that do not look like normal nerve cells. Although this reminds us of a brain tumour, it is not known if these enlarged brains are truly malignant. To qualify as such, they have to be able to metastasize (spread around the body) and kill the animal.

We plan to perform experiments to transplant fragments of brains with overactive Notch to healthy flies and ask whether the transplants will metastasize and kill their host.

We will also use modern genomic tools to look in great detail into the number of genes active in healthy vs tumorous brain tissue. Since the human Notch counterpart is deregulated in many cancers, including brain tumours, this research will help us gain a deeper understanding of how Notch works and how it can trigger cancer.”

Hope for children – understanding why some medullablastoma brain tumours don’t respond to chemotherapy

Professor Taylor in Toronto is working to improve standard treatments for an aggressive form of childhood brain tumour.

Medulloblastomas are one of the most common types of brain tumour to affect children and young teenagers. Despite advances in treatment and survival, they still account for around 1 in 10 of all childhood cancer deaths.

“This type of brain tumour can sometimes spread around the brain and spinal cord, making it very difficult for doctors to treat,” explains Professor Taylor. “Conventional treatment consists of a combination of surgery, chemotherapy and radiation therapy, which often successfully shrinks the original tumour but is less effective at controlling the cancer which has spread.”

In this project Professor Taylor and his team want to find out why chemotherapy treatments sometimes don’t work against these medulloblastoma tumours.

“Understanding why medulloblastoma sometimes fails to respond to chemotherapy is key to developing novel and meaningful therapies.” Says Professor Taylor. “Yet this is often a neglected area of brain tumour research.”

“In this study we will search for the tumour genes which make tumour cells and tumours which have spread ‘chemoresistant’, that is, able to survive chemotherapy treatment. If we can unveil the core mechanisms of chemoresistance in medulloblastoma, this knowledge will contribute to the development of better treatments, and ultimately, we hope, improve survival for children with medulloblastoma.”