August 2016

‘Self-assembling’ molecules send signals that fuel bowel cancer growth

ICR scientists have revealed how a protein called Tankyrase fuels signalling processes responsible for the uncontrolled growth of most bowel cancer cells.

In healthy cells of the bowel lining, Tankyrase helps cells divide normally by turning off a group of proteins called the ‘destruction complex’, which work together to regulate cell division.

But in bowel cancer, one of the most common cancers worldwide, mutations can stop the destruction complex from working properly, allowing proteins that fuel cancer cell growth to build up unchecked.

The research, published in the journal Molecular Cell, used a technique called X-ray crystallography to investigate the 3D structure of a region of Tankyrase called the SAM domain.

The researchers found that the SAM domain helps Tankyrase molecules bind together into intriguing repeating structures which are essential for Tankyrase to recognise and turn off destruction complexes.

If the destruction complex could be switched back on in cancer cells, it could be an important new way to treat the disease.

Study leader Dr Sebastian Guettler said:

“Our study gives important new insights into the structure of Tankyrase, a potential key protein in cancer, and provides new clues about how we might disrupt its activity using future cancer drugs.”

The research was funded by Cancer Research UK and the ICR. 

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September 2016

Blood test predicts response to breast cancer treatment

Test tubes (Jan Chlebik for the ICR, 2011)

Our researchers developed a blood test that can spot which women will respond poorly to current hormonal breast cancer treatments. Women whose test results indicated they were unlikely to respond to hormone drugs could be offered other treatments instead.

The test looks for mutations to a gene called oestrogen receptor 1, or ESR1, in cancer DNA detected in the blood of patients.

These changes indicate that receptors for the hormone oestrogen in the cancer’s cells are switched on permanently, rather than only being activated in response to oestrogen.

If oestrogen receptors are continually switched on, drugs that block the body’s production of the hormone are unlikely to be effective.

The research, published in the Journal of Clinical Oncology, found that women with ESR1 mutations responded better to the drug fulvestrant than to the standard treatment exemestane.

Study leader Professor Nicholas Turner said:

“For the first time we should able to use a potentially simple test to help us pick the best treatment for women with advanced cancer after their initial treatment has failed.”

The research was funded by Le Cure, supporters of The Royal Marsden Cancer Charity, the Medical Research Council, Breast Cancer Now and the NIHR Biomedical Research Centre at The Royal Marsden and the ICR.

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October 2016

Promising drug target for aggressive breast cancers identified

Breast cancer cells (green) invading through a layer of fibroblasts (red). (Luke Henry / the ICR)

Our researchers have identified a molecule that plays a key role in a type of breast cancer called ‘triple-negative’ because it lacks female hormone or HER2 drug targets.

The molecule, called PIM1, could be an exciting target for breast cancer treatments. Researchers hope it may make breast cancer cells more sensitive to treatments like chemotherapy, by influencing their ‘death threshold’.

When faced with chemotherapy, breast cancer cells suffer damage, triggering a signal inside the cell telling itself to self-destruct. This process is essential for effective chemotherapy.

Research teams led by Professor Andrew Tutt at the ICR and King’s College London, and Professor Pascal Meier at the ICR, discovered that the molecule PIM1 is hijacked and over-produced in the majority of triple-negative breast cancers, helping them to survive by making them more resistant to these ‘death signals’.

Professor Tutt said:

“It is early days but as PIM1-inhibitor drugs have already been discovered they may give us a new way to hit these cancer genes.

“We hope to conduct clinical trials in breast cancer, and the hope would be that these drugs could strip triple-negative breast cancers of their defences so that they can be pushed over the cliff by other breast cancer treatments.”

The study was funded by Breast Cancer Now, and published in Nature Medicine.

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November 2016

Scientists discover new inhibitor of cancer stress signal

Scientists at the ICR discovered a way of blocking a crucial safeguard used by cancer cells to stay alive when exposed to stressful conditions.

They designed a powerful new prototype chemical inhibitor of the stress response – which one day could be developed into a drug.

The new inhibitor knocks out a vital set of stress signals regulated by a master control molecule in cells called HSF1. The newly discovered inhibitor was able to block the growth of human ovarian tumours grown in mice. 

The discovery is exciting because HSF1 signals are used by cancer cells across a range of tumour types to stay alive and proliferate when exposed to stressful conditions, but there are currently no drugs that target it. Blocking HSF1 could be effective against many cancers, including drug-resistant forms of ovarian cancer that are currently effectively untreatable.

Study leader Professor Paul Workman, Chief Executive of the ICR, said:

“We’re particularly impressed by the strong effects we see in ovarian cancer cells that are resistant to standard platinum drugs, because drug resistant ovarian cancer is a very difficult condition to treat.”

These findings come from a project funded by Cancer Research UK, Battle Against Cancer Investment Trust and the Cancer Research Technology (CRT) Pioneer Fund and the ICR.

The study was published in the Journal of Medicinal Chemistry.

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December 2016

Scientists reveal ‘safety catch’ within all dividing cells

Image: Dr Chris Bakal 

A study by ICR scientists revealed a ‘safety catch’ within cells that prevents them from dividing until their DNA is allocated equally to the two daughter cells.

This major discovery could lead to new treatments that prevent cancer cells from dividing, or kill them by forcing them to divide prematurely.

Our researchers helped reveal the role of a key molecule called BubR1 which helps to control cell division. The study concluded that a crucial part of BubR1 acts as a safety catch which prevents cell division from progressing until the chromosomes are properly positioned to be pulled apart.

Study leader Professor Jon Pines, Head of Cancer Biology at the ICR, said:

“Our study found a ‘safety catch’ that halts cell division until the cell is ready – and which cancer cells rely on more than normal cells.

“It showed that there is an opportunity to discover new classes of small-molecule drugs that switch off the safety catch, and kill cancer cells by pushing them into premature division.”

The study, published in Molecular Cell, was funded by Cancer Research UK, Wellcome, Science Foundation Ireland and the European Union.

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March 2017

Parkinson’s gene loss of function discovered in one third of cancers

Scientists at the ICR revealed a ‘missing link’ in one of the most commonly activated signalling pathways in cancer.

They showed that PARK2, a gene found in a hereditary form of Parkinson’s disease, is inactivated in a third of all human cancers.

The study showed that loss of PARK2 can stimulate a crucial network of cancer-driving molecules in cells, called the PI3K/Akt pathway.

Our researchers found that this pathway can be ramped up in the stressful, energy-poor conditions often found inside tumours, through inactivation of a well-researched tumour suppressor gene called PTEN.

The team, led by Dr George Poulogiannis, analysed nearly 10,000 tumour samples from 28 different types of cancer, and found that PARK2 was significantly under-expressed across many tumour types.

In mice without working copies of PARK2, mutations to PTEN resulted in a much higher risk of developing tumours than mice with working copies and poorer survival outcomes.

Study leader Dr George Poulogiannis said:

“In the future, tests that look for mutations to the PARK2 gene may help to identify patients who have particularly aggressive forms of cancer that may respond to inhibitors of PI3K/Akt signalling.”

The study, funded in the UK by the ICR, was published in Molecular Cell and could help researchers understand how aggressive cancer cells can survive and proliferate in low energy conditions.

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April 2017

3-in-1 blood test opens up precision medicine for prostate cancer

Scientists have developed a three-in-one blood test that could transform treatment of advanced prostate cancer – by guiding the use of precision drugs.

By testing cancer DNA in the bloodstream, researchers at the ICR and The Royal Marsden NHS Foundation Trust found they could firstly target drugs called PARP inhibitors at men most likely to benefit. Secondly, the test could also pick up early signs of the drugs not working – and finally, it could monitor for later development of resistance.

The test looks for errors in genes involved in repairing DNA. Cancer cells with these errors are vulnerable to PARP inhibitors.

The study, published in Cancer Discovery, examined blood samples from 49 men at The Royal Marsden enrolled in the TOPARP-A phase II clinical trial of PARP inhibitor olaparib.

Study leader Professor Johann de Bono said:

“Our study showed that as well as selecting patients for treatment with the precision drug olaparib, our test can also identify genetic changes that allow prostate cancer cells to become resistant.

“Not only could the test have a major impact on treatment of prostate cancer in the future, but it could also be adapted to open up the possibility of precision medicine to patients with other cancer types.”

The study was funded by the Prostate Cancer Foundation, Prostate Cancer UK, The Movember Foundation, Cancer Research UK and the National Institute for Health Research (NIHR) via the Experimental Cancer Medicine Centre Network, and the NIHR Biomedical Research Centre at The Royal Marsden and the ICR.

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May 2017

New genetic cause of kidney cancer in children discovered

Scientists at the ICR have identified a new genetic cause of Wilms tumour, a childhood kidney cancer.

Our researchers used a technique called exome sequencing to analyse all the genes in 20 families with a genetic disorder called mosaic variegated aneuploidy (MVA) syndrome, which has been linked to Wilms tumour.

They found mutations in a gene called TRIP13 in three of these families, and went on to discover errors in the same gene within other families affected by Wilms tumour, but not MVA.

The study, which was led by the ICR’s Professor Nazneen Rahman in collaboration with the Hubrecht Institute-KNAW, will help parents understand why their children have developed cancer and provide information about the risk of cancer for other children.

Professor Nazneen Rahman said:

“This study has been of immediate use to families in providing a reason for why their child developed cancer, and information about risks to other children, which is very rewarding.

“Equally importantly, the study has provided new information about how aneuploidy and cancer are linked – a topic that has been hotly debated and intensively researched for many decades.”

This study was funded by Wellcome, the Netherlands Organisation for Scientific Research and the Dutch Cancer Society, and was published in Nature Genetics.

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June 2017

Early abiraterone treatment improves prostate cancer survival

A major new clinical trial showed that adding abiraterone to hormone therapy at the start of prostate cancer treatment improves survival by 37%.

The findings, published in the New England Journal of Medicine, could change the standard of care for men with prostate cancer.

They come from one of the largest ever clinical trials for prostate cancer, called STAMPEDE, which involved several leading researchers from the ICR and The Royal Marsden.

In the trial, half of the men were treated with standard hormone therapy, while the other half received hormone therapy and abiraterone. Abiraterone, which was discovered at the ICR, is usually given to men with advanced prostate cancer that has spread and has stopped responding to standard hormone therapy. 

Men who were given abiraterone were 70% less likely to experience progression in their disease over the course of three years than those receiving hormone therapy. They were also 37% more likely to still be alive.

Study author Professor Johann de Bono said:

“These results show that abiraterone used at the start of treatment has clear benefits for patients. I really hope these results can change clinical practice.”

The STAMPEDE trial was funded by Cancer Research UK and the Medical Research Council (MRC).

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July 2017

Immunotherapy kinder than chemotherapy for head and neck cancer

Our researchers found that the immunotherapy nivolumab was kinder than chemotherapy for people with advanced head and neck cancer – leading to better quality of life for patients.

Immunotherapies spark the immune system into action against cancers, and are seen as an exciting new approach for treating some tumour types.

We already knew that use of nivolumab in people with recurrent or metastatic head and neck cancer greatly increased survival.  

In this major phase III clinical trial, led by Professor Kevin Harrington of the ICR and The Royal Marsden NHS Foundation Trust, our researchers found that nivolumab also helps them maintain a better quality of life for longer.

The study compared nivolumab with standard chemotherapies, and asked patients to report their physical symptoms, mental health and general wellbeing. Patients on nivolumab gave consistently better ratings throughout the trial.

Professor Harrington said:

“We now need to test if we can move away from resorting to traditional chemotherapies, which come with far too much collateral damage, and see these smarter, kinder therapies used as a first-line treatment to replace chemotherapy altogether.”

The study, published in The Lancet Oncology, was funded by Bristol-Myers Squibb, with support from the NIHR Biomedical Research Centre at The Royal Marsden and the ICR.

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