Worldwide Cancer Research Menu

Patching up tumour blood vessels

For a tumour to grow beyond a certain size it needs to be connected to the blood supply. Once this happens the cancer cells also have a route to escape and travel to other organs in the body. At this stage cancer is much more difficult to treat so it’s vital that we find ways to stop this from happening.

Dr Pipsa Saharinen and her team at the University of Helsinki recently discovered molecular mechanisms that cause blood vessels to become unstable. This ‘vessel leakiness’ is a stepping stone towards new blood vessels developing and is a crucial factor in tumours becoming connected to the blood supply.

Using funding from Worldwide Cancer Research, Dr Saharinen now wants to study in detail these molecular mechanisms, to find a weak spot that can be knocked out to prevent abnormal blood vessels. The hope is that this could ultimately lead to the development of new treatments that can prevent the spread of cancer.

Switching off DNA repair in cancer cells

Dr Maria Tresini is using funding from Worldwide Cancer Research to study an innovative way to switch DNA repair mechanisms off in cancer cells so that they can’t fix their damaged DNA causing them to die. Dr Tresini’s lab recently discovered a whole new molecular mechanism that cells have in their repertoire for DNA repair and now want to understand exactly how this mechanism works to see if can be exploited for cancer therapy.

The DNA in your cells is subjected all the time to damage that can lead to genetic mutations that cause cancer. In fact, research suggests that the DNA in each of your cells becomes damaged 20,000 times a day. It’s a good thing that our cells come equipped with multiple defence mechanisms that detect damaged DNA and repair it. But these repair mechanisms are also responsible for keeping cancer cells alive when they suffer DNA damage, including damage caused by chemotherapeutic drugs.

Dr Tresini is focusing on something called ‘R-loops’ - molecular structures that occur naturally when DNA becomes damaged. These R-loops are intriguing because they activate the DNA repair process in cells but at the same time make the DNA molecule unstable and more susceptible to damage. By understanding exactly how R-loops activate DNA repair it will be possible to identify ways to block the process with drugs. This could lead to a build-up of DNA damage in cancer cells that ultimately causes the cell to die.

Unpicking the role enzymes called sirtuins play in cancer

Dr Alejandro Vaquero and his team in Barcelona are trying to understand how a group of enzymes, known as Sirtuins, plays a role in the formation of tumours. They hope that by understanding more about these enzymes they will uncover ways to target them for cancer treatment.

Sirtuins are a set of enzymes that allow the cell to respond to environmental stressors such as hyperoxidative conditions, metabolic alterations or any DNA damaging conditions such as irradiation or damaging chemicals. These stress conditions are very relevant as they have been shown to contribute to tumour development. Sirtuins can influence the cell to respond in varied ways depending on the severity of the stress condition faced by the cell. Under certain circumstances Sirtuins will allow cells to adapt and survive but if the stress reaches dangerous levels Sirtuins can also instruct the cell to die. Due to these complex roles, alteration of some Sirtuins can help prevent tumours forming whereas others can actively help promote them. This complexity is in part due to the fact that some Sirtuins show two distinct enzymatic activities. Dr Vaquero wants to understand this enzymatic diversity and the specific contribution of each of these activities to the role of Sirtuins in cancer.

Drugs that block Sirtuins are already showing promise in clinical trials but because the enzymes have such a broad biological role there are many toxic side effects. Understanding more about these enzymes, including discovering new targets, could help identify better ways to target them and reduce side effects in patients.

Disrupting a cellular communication network

Dr Thomas Vaccari at the Department of Biosciences of the University of Milan in Italy, is using funding from Worldwide Cancer Research to identify weaknesses in a specific cellular communication network, called Notch signalling, which is implicated in a variety of cancers.

His team are using fruit flies to understand more about how this communication network functions. The gene Notch was discovered in the fruit fly but it turned out that the role it plays in normal development, growth, and even in the generation of tumours, is similar to the role it plays in humans. Dr Vaccari hopes that their research will reveal more information about the biological processes that Notch controls, which will ultimately lead to the discovery of a better understanding of its role in cancer.

Shutting off cancer’s energy supply

Dr Angel Nebreda and his team at the IRB in Barcelona are using funding from Worldwide Cancer Research to find out how cancer cells get their energy so that they can find ways to shut them down. Cancer cells are known to obtain their energy through different mechanisms to normal cells so understanding how they do it could reveal new ways to develop targeted treatments.

The team are particularly interested in a protein called p38-alpha MAPK, which they have begun to show plays a central role in the survival of cancer cells. They now want to study in greater detail exactly how this protein helps cancer cells to produce the energy they need to grow and divide and what happens to cancer cells if they try and block it off.

Developing drugs for repairing a protein that is key in cancer prevention

Professor Hartmut Luecke at the University of Oslo is using funding from Worldwide Cancer Research to develop new drugs that can reactivate a defunct protein found in over 50% of all cancers. A drug that can kick this protein, called p53, back into action has the potential to be a highly targeted treatment for many different types of cancer.

Using their expertise in biochemistry, the Luecke lab have already produced drug molecules that are able to correct a common fault in p53, which they now want to take forward with further testing. Ultimately, they hope to identify the most effective drug molecule that in the future could be taken into clinical trials. The team will start off by creating a variety of drug molecules with slightly different chemical structures to find out which one is the most effective at reactivating p53. They will then test how good this drug is at killing cancer cells in the lab – a necessary stage before the drug can be tested in animals and then patients.

Gene-editing stem cells to improve immunotherapies

Immunotherapies for cancer are hot topic at the moment. And if you follow the news you’ll know gene-editing using the recently discovered CRISPR technology is also high on the agenda. Dr Pierre Guermonprez, based at King’s College London, is interested in using a bit of both with his grant from Worldwide Cancer Research.

Dr Guermonprez and his team want to see if they can use gene-editing to technology to engineer a special type of immune cell, called a dendritic cell, which could be used to help boost a person’s immune system in order to make other treatments work more effectively. They plan to develop new laboratory methods for coaxing stem cells (these cells are capable of becoming any cell in the body) to turn into dendritic cells that could be used for therapy. Using this method they will then be able to tweak the genetics of the stem cells using CRISPR to see if they can produce dendritic cells that are able to induce a strong immune response. The development of these novel techniques will hopefully pave the way for the development of a new type of cancer therapy that could bolster the strength of other drugs.

Using worms to improve the use of chemotherapy

Cisplatin is a widely used chemotherapy drug that works by damaging the DNA of cells to the extent that the cell cannot repair itself and dies. However, even after successful treatment, cancers often return because some of the cancer cells are able to repair the damage caused by cisplatin and survive. Professor Anton Gartner and his team at Dundee University are trying to identify the molecular machinery that cells use to repair damage caused by cisplatin. By doing this they hope it will lead to better ways to identify patients that would benefit the most from the drug.

Professor Gartner is using the microscopic nematode worm (C. elegans) to test how cisplatin interacts with DNA and what happens once damage is induced. These worms are a useful model because they contain only around 1000 cells and their genetics are very well understood. This means the team can easily study the changes that occur to DNA following cisplatin in a whole organism.

Do dietary fats help cancer spread?

Could your diet play a role in helping cancer to spread? This is the question being tackled by Professor Salvador Aznar-Benitah at the IRB in Barcelona. His team are using funding from Worldwide Cancer Research to understand how fatty acids (fragments of fats or oils) enable cancer cells to colonise other organs in the body once they have spread from the original tumour (a process called metastasis). They are also testing a new treatment that could help clamp down on these cells before they have chance to spread.

Result from a previous Worldwide Cancer Research grant revealed that metastatic cancer cells stand out from the crowd because they have a particular protein, called CD36, on their surface. It turns out that certain fatty acids react with this protein and increase the metastatic potential of the cancer cell. Professor Aznar-Benitah wants to understand in more detail what the exact mechanism behind this phenomenon in the hope of developing ways to target it with treatments. His team have developed an experimental drug that can target CD36 and they will be testing this in mouse models of oral cancer, melanoma and breast cancer to see if they can develop an effective drug for further development.

Plugging the gap in the ”guardian of the genome”

Professor John Spencer at the University of Sussex is using funding from Worldwide Cancer Research to drive a drug discovery program that aims to develop a new cancer drug that re-activates “the guardian of the genome” and causes cancer cells to die. Professor Spencer’s new drug targets a fault in a protein called p53 that is found in around 100,000 new cancer cases each year. This means the drug has the potential to treat up to 100,000 people that are diagnosed with cancer every year.

Using previous funding from Worldwide Cancer Research, Professor Spencer and his team developed a library of chemical compounds that were able to switch p53 back on in cancer cells that carried a specific faulty version of the protein. This fault is like a missing brick in a wall causing it to become unstable. This “gap” in the protein causes it to break down before it has chance to activate apoptosis. The compounds the lab created “plug the gap” in the faulty p53 protein and stabilise it, allowing normal function to be resumed.

The team now want to identify the compounds from their library that are the most likely to succeed in becoming a new cancer drug. They will run tests on the toxicity of the drugs to help make sure that negative side effects are reduced, they will test the selectivity of the drugs to ensure that the ones they pick are targeted towards cancer cells with the faulty p53 and won’t harm normal cells, and they will find ways to improve the chemical structure of the drugs so that they can be as effective as possible. Ultimately, this research could lay the foundations towards the future development of a brand new drug capable of targeting a wide range of cancers.