Worldwide Cancer Research Menu

A potential new drug target for a deadly form of leukaemia

Acute myeloid leukaemia (AML) is a relatively rare form of leukaemia with around 350,000 people worldwide diagnosed each year. Although rare, survival rates are low, with only around 15% of people surviving the disease for more than 5 years after diagnosis.

Professor Suzanne Cory based at The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, is studying the role of MNT, an antagonist of the protein MYC, to explore its role in enabling AML cells to stay alive in the body. By unravelling the molecular connections that link MNT to cancer, they hope to discover a new target for drug development for AML.

Understanding why children with Down Syndrome are at risk of leukaemia

Down Syndrome is a genetic disorder caused by an additional copy of the chromosome 21. The disorder is estimated to effect 1 in every 1000 live births worldwide. Children with Down Syndrome are at greater risk of developing blood cancers, but the underlying biological mechanisms for this are unclear. In particular, the incidence of a type of blood cancer called acute megakaryoblastic leukaemia (AMKL) is 500 times more prevalent in children with Down Syndrome.

Dr Andrea Ditadi and his team based at Fondazione Centro San Raffaele, Milan, Italy, propose to uncover this mystery by carrying out in-depth studies on pluripotent stem cells – the cells that “give birth” to all the cell types in our body. By studying these cells they want to find out how the cells of the blood system develop in Down Syndrome and use this to identify the cells responsible for AMKL development. This fundamental understanding of the biology behind this phenomenon will ultimately lead to new ways to diagnose and treat AMKL.

Developing targeted immunotherapy for leukaemia

There are nearly 440,000 new cases of leukaemia diagnosed worldwide each year and less than half of these people will survive for 10 years or more after their diagnosis. The current therapies for leukaemia are often very successful at treating patients, but many people go on to develop the disease again further down the line.

Dr Giulia Casorati based at Fondazione Centro San Raffaele in Milan, Italy, has recently discovered a new immunotherapy technique that forces cells of the immune system to recognise, attack and destroy leukaemia cells. Dr Casorati and her team now want to see if they can develop this technique further by focusing their attention on a powerful immune cell called a Natural Killer T-cell. Their project aims to genetically engineer Natural Killer T-cells so that they recognise leukaemia cells and test their cancer killing ability in the lab. They hope that their technique will one day be turned into a new treatment for leukaemia.

Visualising molecular messengers in chronic lymphocytic leukaemia

There are around 440,000 new cases of leukaemia diagnosed worldwide each year and around a quarter of these are a type called chronic lymphocytic leukaemia (CLL). CLL is a cancer of a type of white blood called a B-lymphocyte. The surface of a B-lymphocyte is coated with a unique protein called a “B-cell receptor”, which act as a messenger, carrying molecular information from the outside of the cell to the inside. Once inside, the molecular message instructs the cell what to do by activating or deactivating genes. In CLL, the B-cell receptors are overactive causing uncontrolled growth and division of the lymphocytes.

Blocking the molecular signals transmitted into the cell from B-cell receptors is a promising therapeutic strategy for treating CLL patients, but the drugs that have designed to do this don’t work for every patient and can have unwanted side effects. Dr Massimo Degano, based at Fondazione Centro San Raffaele in Milan, is studying the varied molecular structures of B-cell receptors to understand why this is the case.

Using sophisticated chemical techniques, the team will work out the 3-dimensional structure of the different types of B-cell receptor, before using this information to identify drugs that can interact with the B-cell receptor and stop it working in CLL.

Understanding stem cells in leukaemia

Dr Marc Raaijmakers and his team at Erasmus MC in the Netherlands are working out how blood cancers develop in the bone marrow so that they can find new ways to treat the disease. Myelodysplastic syndrome is one of the most common pre-cancerous stages that can lead to the development of blood cancers (leukaemia).

The bone marrow is where new blood cells are made and within it there are many different types of cell. One in particular, called a ‘mesenchymal cell’, is thought to be one that can contribute to the development of myelodysplastic syndromes. Dr Raaijmakers wants to know more about how these cells do this and understand the molecular factors that cause it to happen. The team, including Dr Peter de Keizer, hopes that this will lead them to discover new ways to ‘reverse’ the cancer promoting environment in the bone marrow and stop blood cancer in its tracks.

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.”

Flipping the switch on cancer cell death

Dr Huntly and his team are using Worldwide Cancer Research funding to understand more about the blood cancer acute myeloid leukaemia (AML). He will investigate how two specific proteins may interact with and modulate HOXA9, a protein known to drive around half of all AML cases.

Around 34% of patients diagnosed with leukaemia in the UK have AML, yet there are few effective treatment options available. This is partly because many different cell DNA mutations are linked with AML, and it is hard for scientists to develop treatments that effectively target them all.

HOXA9 represents a single piece in the puzzle, linking a number of AML-triggering DNA mutations with ultimate development of the disease. HOXA9 expression is also linked to aggressive disease. However, scientists still do not know exactly how this happens.

Dr Huntly wants to find out how two proteins that his team have demonstrated to physically bind to HOXA9, and which seem to modulate leukaemia cell growth in the lab, could be involved in the process. He will use a three-pronged approach to study this problem. First he will look at how these proteins behave together at a molecular level, before then using cell-based models and mice to study how they may interact in leukaemia.

"If this research is successful," says Dr Huntly, "it will set the scene for targeting the interactions between these three proteins, as a much needed potential novel therapeutic in AML."

Investigating the role of genomic ‘dark matter’ in chronic lymphocytic leukaemia

Dr Martin-Subero is investigating how changes in genomic ‘dark matter’ could increase risk of chronic lymphocytic leukaemia (CLL)- one of the most common types of leukaemia.

In the UK alone more than nine new cases of CLL are diagnosed every day. Scientists don’t yet know exactly how the disease starts, and several large studies have recently started homing in on potential areas of the human genome which might be linked to CLL. Early data suggest that changes in the ‘dark’ regions of the genome which surround the genes could be important. For years many scientists thought these areas contained nothing but unused ‘junk DNA’. Now more and more studies show these areas actually have many important roles regulating how genes are switched on and off.

In this new project Dr Martin-Subero and his team will use data from these large studies along with data they have generated themselves to study in detail exactly how changes to the areas surrounding genes might impact CLL development. They will map the DNA landscape of these areas and work out how nearby mutations and external ‘epigenetic’ mechanisms might influence gene activity. Through this work they hope they will also identify new CLL genes.

“Our ultimate aim for this project is to study in patients which of these newly identified genetic or epigenetic changes might have real clinical potential for targeting with new treatments,” explains Dr Martin-Subero.

Investigating the role of stem cells in leukaemia in order to develop more effective treatments

Professor Van Vlierberghe is investigating in detail how pre-leukaemic stem cells develop and can lead to a more aggressive form of leukaemia.

Pre-leukemic stem cells are the very first blood cells which can ultimately lead to leukaemia. They are also more resistant to chemotherapy and radiation therapy, so scientists suspect that the presence of these cells in a patient’s cancer might lead to more aggressive forms of the disease, or cancer which relapses following treatment.

But scientists don’t yet know exactly how pre-leukaemic stem cells develop. That’s why in this project Professor Van Vlierberghe aims to better understand the underlying molecular mechanisms which control these cells and their ability to divide continuously.

“We hope the findings from this study will ultimately help us to develop more effective targeted therapies for the treatment of aggressive subtypes of human leukaemia,” says Professor Van Vlierberghe.

The Notch pathway in T-Acute Lymphoblastic Leukemia

Every function within our cells is controlled by specific molecules. These molecules are in turn controlled by other molecules, and those ones by yet more molecules. These are called pathways, as one molecule being turned on or off leads to the same happening in the next molecule in the pathway etc.

We already know about many such pathways, how they work, and affect different functions within our cells. Notch1 is one of the molecules involved in the Notch pathway. The Notch pathway plays a part in the development of a type of cancer called T-Acute Lymphoblastic Leukemia (T-ALL). T-ALL is a rare type of leukaemia that generally affects older children and teenagers. It is an aggressive disease that progresses quickly, and affects T cells, which are white blood cells that are part of our immune system. Until now, the knowledge that the Notch pathway is needed for T-ALL development has not lead to any treatments because we need to know more about how it works and what parts of it might be blocked by a drug.

Dr Bigas and her team have found that other pathways are essential in cooperation with Notch1 to cause T-ALL in mice. They will be using their Worldwide Cancer Research grant to study how the Wnt pathway affects Notch and its ability to cause T-ALL. They will study what happens further along these pathways during T-ALL development, with the hope of identifying new ways to treat this disease.