̽��ֱ�� of Cambridge - Kay Kendal Leukaemia Fund

Scientists develop new class of cancer drug with potential to treat leukaemia

cjb250 — Mon, 26 Apr 2021 15:00:17 +0000

Our genetic code is written in DNA, but in order to generate proteins – molecules that are vital to the function of living organisms – DNA first needs to be converted into RNA. ̽��ֱ��production of proteins is controlled by enzymes, which make chemical changes to RNA. Occasionally these enzymes become mis-regulated, being produced in over-abundance.

In a study published in 2017, a team led by Professor Tony Kouzarides from the Milner Therapeutics Institute and the Gurdon Institute at the ̽��ֱ�� of Cambridge showed how one such enzyme, METTL3, plays a key role in the development and maintenance of acute myeloid leukaemia. ̽��ֱ��enzyme becomes over-expressed – that is, over-produced – in certain cell types, leading to the disease.

Acute myeloid leukaemia (AML) is a cancer of the blood in which bone marrow produces abnormal white blood cells known as myeloid cells, which normally protect the body against infection and against the spread of tissue damage. AML proceeds rapidly and aggressively, usually requiring immediate treatment, and affects both children and adults. Around 3,100 people are diagnosed with the condition every year in the UK, the majority of whom are over 65 years of age.

Now, Professor Kouzarides and colleagues at STORM Therapeutics, a Cambridge spinout associated with his team, and the Wellcome Sanger Institute, have identified a drug-like molecule, STM2457, that can inhibit the action of METTL3. In tissue cultured from individuals with AML and in mouse models of the disease, the team showed that the drug was able to block the cancerous effect caused by over-expression of the enzyme.

Professor Kouzarides said: “Proteins are essential for our bodies to function and are produced by a process that involves translating our DNA into RNA using enzymes. Sometimes, this process can go awry with potentially devastating consequences for human health. Until now, no one has targeted this essential process as a way of fighting cancer. This is the beginning of a new era for cancer therapeutics.”

To investigate the anti-leukaemic potential of STM2457, the researchers tested the drug on cell lines derived from patients with AML and found that the drug significantly reduced the growth and proliferation of these cells. It also induced apoptosis – ‘cell death’ – killing off the cancerous cells.

̽��ֱ��researchers transplanted cells from patients with AML into immunocompromised mice to model the disease. When they treated the mice with STM2457, they found that it impaired the proliferation and expansion of the transplanted cells and significantly prolonged the lifespan of the mice. It reduced the number of leukaemic cells in the mouse bone marrow and spleen, while showing no toxic side effects, including no effect on body weight.

Dr Konstantinos Tzelepis from the Milner Therapeutics Institute at the ̽��ֱ�� of Cambridge and the Wellcome Sanger Institute added: “This is a brand-new field of research for cancer and the first drug-like molecule of its type to be developed. Its success at killing leukaemia cells and prolonging the lifespans of our mice is very promising and we hope to begin clinical trials to test successor molecules in patients as early as next year.

“We also believe that this approach – of targeting these enzymes – could be used to treat a wide range of cancers, potentially offering us a new weapon in our arsenal against these terrible diseases.”

Michelle Mitchell, Chief Executive of Cancer Research UK, said: "This work is yet another example of how our researchers strive to get new cancer treatments into the clinic and improve outcomes for cancer patients.

"Acute myeloid leukaemia is an aggressive form of cancer which grows rapidly. Treatment is required as soon as possible after diagnosis, which means research like this can't come soon enough.

"We look forward to seeing the outcomes of the phase 1 trial and the benefits it may have for AML sufferers and their families in the future."

̽��ֱ��research was supported by Cancer Research UK, the European Research Council, Wellcome, the Kay Kendall Leukaemia Fund, and Leukaemia UK.

STORM Therapeutics is a ̽��ֱ�� of Cambridge spin-out, supported by Cambridge Enterprise. It specialises in translating research in RNA epigenetics into the discovery of first-in-class drugs in oncology and other diseases.

Reference
Yankova, E, et al. Small molecule inhibition of METTL3 as a therapeutic strategy for acute myeloid leukaemia. Nature; 26 Apr 2021; DOI: 10.1038/s41586-021-03536-w

Scientists have made a promising step towards developing a new drug for treating acute myeloid leukaemia, a rare blood disorder. In a study published today in Nature, Cambridge researchers report a new approach to cancer treatment that targets enzymes which play a key role in translating DNA into proteins and which could lead to a new class of cancer drugs.

Until now, no one has targeted this essential process as a way of fighting cancer. This is the beginning of a new era for cancer therapeutics

Tony Kouzarides

National Cancer Institute

Human cells with acute myelocytic leukemia, shown with an esterase stain at 400x

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Researchers discover new test for chronic blood cancers

sj387 — Tue, 10 Dec 2013 15:27:54 +0000

A simple blood test will soon be able to catch the vast majority of a group of chronic blood cancers, a new study reveals. Although around 60 per cent of cases can be identified with the current blood test, scientists did not know what caused the other cases and therefore could not test for it. Cambridge researchers have now identified a new cancer gene which accounts for the other 40 per cent of these chronic blood cancers. ̽��ֱ��research was published today, 10 December, in the New England Journal of Medicine.

Professor Tony Green, from the ̽��ֱ�� of Cambridge’s Cambridge Institute for Medical Research and Department of Haematology, who led the research said: “Diagnosing these chronic blood cancers is currently difficult and requires multiple tests, some of which are invasive and painful. Now, most patients with a suspected blood cancer will be able to be given a diagnosis after a simple blood test.”

This group of chronic blood cancers – which affect an estimated 30,000 people annually in the UK – cause the over-production of red blood cells and platelets. These changes result in an increased incidence of blood clots which can be devastating when strokes or heart attacks occur. Although many patients can live for years with few or no symptoms, in some patients the disorders can become more aggressive with time and may even develop into acute leukaemia.

In 2005 scientists identified the JAK2 gene, mutationt in which are associated with around 60 per cent of blood cell disorders. Based on these findings a blood test was developed which transformed the way these blood disorders are diagnosed. Unfortunately, because the gene was only found in a little over half of people with chronic blood cancers, individuals who tested negative for the JAK2 gene would then have to undergo a battery of protracted, invasive testing to determine if they indeed had one of these disorders.

In the new study, led by the ̽��ֱ�� of Cambridge and the Wellcome Trust Sanger Institute and supported by Leukaemia & Lymphoma Research together with the Kay Kendall Leukaemia Fund, scientists identified a new gene, CALR, which is altered in the other 40 per cent of blood disorders. For the research, the scientists sequenced the DNA of patients with chronic blood disorders. By analysing the DNA sequence, they were able to identify CALR as a new cancer gene which, when mutated, results in chronic blood cancers. Additionally, they found that patients with the CALR mutation – unlike those with the JAK2 mutation – had higher platelet counts and lower haemoglobin levels.

Peter Campbell from the Sanger Institute, who co-led the research, said: “There is now a sense of completeness with these disorders – the vast majority of our patients can now have a definitive genetic diagnosis made. In the next year or two, we will see these genetic technologies increasingly used in the diagnosis of all cancers, especially blood cancers.”

Dr Jyoti Nangalia co-first author of the study from the ̽��ֱ�� of Cambridge said: “Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments – just as the discovery of JAK2 did. ̽��ֱ��CALR gene is involved in a cell function – aiding with the folding of proteins made by the cell - which has not implicated in these disorders before, so our research raises as many questions as it answers.”

A new test for blood cancers will catch many more cases than the present test that identifies only 60 per cent.

Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments

Dr Jyoti Nangalia

Nephron

Micrograph of a plasmacytoma, a hematological malignancy

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Cut-and-paste cancer: lymphoma’s genetic blueprint

bjb42 — Mon, 04 Jan 2010 14:32:32 +0000

Lymphoma is an umbrella term that describes cancer of the white blood cells of the lymphatic system, which normally acts to protect the body against infection. In lymphoma, malignant changes in a white blood cell causes it to divide abnormally and out of control; not only are these cells unable to protect the body against infection, and in fact interfere with the growth of healthy cells, but they also build up, often in lymph nodes, as tumours.

Lymphoma accounts for more than 9,000 new cancer cases diagnosed each year in the UK alone and the incidence is rising by about 4% per year. Some of these cases appear to result following viral infections, immunodeficiency or autoimmunity, but for the most part we don’t know what causes the genetic alterations underlying the different subtypes of lymphoma, of which over 30 are now known. However, progress is being made in understanding what effect the genetic alteration has on the cell in which it occurs.

Dr Suzanne Turner leads a group in the Department of Pathology who are interested in a subtype of lymphoma that, although rare, has become a paradigm for understanding the growth and development of lymphomas (lymphomagenesis) because of its well-defined genetic alteration.

̽��ֱ��many different subtypes of lymphoma have alterations that range from single mutations, through loss and gain in regions of genetic material, to large-scale chromosomal changes. ̽��ֱ��cancer that interests Dr Turner, anaplastic large cell lymphoma (ALCL), falls into this last category because it results when sections of genetic material from two chromosomes are essentially ‘cut and pasted’ in the wrong place.

Genesis of a lymphoma

Although relatively rare in adults, ALCL accounts for 1 in 10 cases of all lymphomas in children. ̽��ֱ��most common type of ALCL is caused by the swapping of genetic material between chromosomes 2 and 5. Rather like the joining together of parts of two different sentences, swapping segments of chromosomes can sometimes result in nonsense. But in some cases, the two parts produce an intelligible outcome, albeit with a different meaning. This is what happens in ALCL: the altered genetic code, which juxtaposes the gene for nucleophosmin (NPM) on chromosome 5 with the gene for anaplastic lymphoma kinase (ALK) on chromosome 2, generates a new gene product (NPM-ALK) at the fusion point between the two chromosomes. Although only portions of the two genes remain, together they create a new protein with altered functions.

Dr Turner’s group was one of the first research groups in the world to demonstrate that NPM-ALK can cause cancer. They discovered that the errant protein sets off a cascade of events that confers survival and growth properties on the cells in which it is expressed. ̽��ֱ��cells proliferate uncontrollably and a lymphoma is born.

A model system

Dr Turner’s group has developed model systems to investigate both the specific cell type in which the translocation and disease originate and whether the normal functions of the immune system contribute to the disease process. Potential new drugs and drug combinations, particularly those that inhibit the NPM-ALK protein, are being tested with the long-term aim of taking these into the clinic. A collaboration with Dr Amos Burke, Consultant Oncologist within the Department of Paediatric Haematology and Oncology at Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, provides an important clinical perspective on the work. And new imaging methods developed by Professor Kevin Brindle in the Cambridge Research Institute are being used to detect treatment response at an early stage.

For ALCL, the long-term goal is to develop a way of inhibiting NPM-ALK and the catastrophic malignant effects that it initiates within the white blood cell in which it occurs. But these studies will also complete a story – one that explains the way in which lymphoma can be set in motion… and be stopped in its tracks.

For more information, please contact Dr Suzanne Turner (sdt36@cam.ac.uk) at the Division of Molecular Histopathology in the Department of Pathology. Dr Turner is a Leukaemia Research Bennett Fellow and is also funded by the Kay Kendal Leukaemia Fund and Cancer Research UK.

Researchers in the Department of Pathology have established precisely how the ‘cutting and pasting’ of genetic material from one chromosome to another results in cancer.

Suzanne Turner

Lymphoma

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