Worldwide Cancer Research Menu

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.

Investigating the role of immune system cells in cancer

The immune system constantly monitors the body for signs of anything that may cause disease, including cancer. White blood cells are the main cells that run the immune system, and one type of white blood cell is called a natural killer (NK) cell. These cells have molecules on their surface, called receptors, which recognise viruses or tumour cells. There are several such receptors, and they are involved in switching on, or waking up, NK cells when the body comes under attack. The genes that control these receptors have been shown to influence how patients react to treatment. Some specific genes appear to have a big effect on the outcome of patients who have received a stem cell transplant to treat a type of cancer called acute myeloid leukemia (AML). Patient outcomes were dependent on the types of genes that different patients had.

With his new Worldwide Cancer Research grant, Professor Rossjohn is planning to study the structure of these NK cells receptors and how they interact with other molecules, in order to learn how they recognise tumour cells. These results will hopefully help to reinterpret results from stem cell transplant patients so that in future better matches can be found when selecting stem cell donors for diseases that affect the blood or bone marrow, such as AML.

Studying yeasts to identify new human targets for chemotherapy

Hydroxycarbamide is a drug that stops cells from making and repairing DNA, it affects a molecule called RNR. It is used as a common treatment in cancers that cause the abnormal growth of blood cells in the bone marrow, for example acute myeloid leukemia (AML). In AML it helps to reduce the number of cancerous cells but the disease cannot be controlled for very long, as resistance to the drug often occurs. The use of hydrocarbamide against other cancer types is also being investigated, but until now little is known about how it stops cancer cells from growing or how they become resistant to the drug. In yeasts, two mechanisms that control RNR have been identified and are widely known.

Now new research carried out by Professor Carr, also in yeast, has revealed a possible third mechanism. His Worldwide Cancer Research grant will be used to study how these three mechanisms work and attempt to find equivalent human molecules that could control RNR. This would potentially identify new molecules that could be turned on or off for use in chemotherapy.

Using sirtuins to treat cancer

Many chemotherapy drugs already exist to treat different types of cancer, but unfortunately tumour cells often become resistant to the drug after a period of time. Dr Lan and her team previously discovered a small anti-tumour molecule called tenovin-6. They found that tenovin-6 was able to stop two proteins called sirtuin 1 and sirtuin 2. More recently, other research groups have shown that tenovin-6 can kill stem cells that cause a type of cancer called chronic myelogenous leukemia (CML), specifically the stem cells which have become resistant to a type of chemotherapy drug called imatinib (also known as Glivec). It is essential to get rid of these stem cells to avoid the cancer coming back. It is believed that tenovin-6 kills these cells by stopping the sirtuin 1 protein, which is found at very high levels in CML stem cells.

Dr Lan and her team recently identified new molecules that are similar to tenovin-6 that also affect sirtuin 1 and 2. They will use their new grant to carry out further tests on these molecules as well as other tenovin molecules to understand how they work. They will also carry out further tests looking at the new molecules in combination with imatinib to see might be used to enhance imatinib treatment.

Investigating acute promyelocytic leukemia (APL)

Professor Salomoni and his colleague Professor de Thé are using their Worldwide Cancer Research grant to study Acute Promyelocytic Leukaemia (APL).  APL is a cancer of our white blood cells, in this case myeloid cells.  White blood cells are a vital part of our immune system where they help fight infection.  APL is a type of Acute Myeloid Leukaemia but is treated differently and it is very aggressive and progresses quickly.  It is rare in young children but can affect adults of any age which is unusual as most cancers occur in older people.  Around 200 adults are diagnosed with APL every year in the UK alone.

Every cell in our body contains thousands of genes that control most of the activities in the cell.  In some cancers, including leukaemia, one gene can become fused or ‘glued’ to the end of another one, creating a hybrid gene.  Professor Salomoni will be looking at one of these hybrid genes and a molecule called DAXX and their role in causing APL.  DAXX has been implicated in other human cancers, such as tumours of the pancreas and brain, and works by modifying the way the DNA is packed in the cell. APL is one of the success stories of cancer therapy, with the majority of people with APL now surviving the disease. However, by better understanding how APL develops, in the future, scientists can then take this information and try to find ways to stop it from occurring or detect it earlier or to better treat it. Furthermore, this information will potentially provide new clues on how to treat other cancers characterized by similar disease mechanisms.