January 2018

Scientists zoom in to watch DNA code being read

 

Our scientists have unveiled incredible images of how the DNA code is read and interpreted – revealing new detail about one of the fundamental processes of life.

The mechanism for reading DNA and recoding it into RNA is common to all animals and plants, and is often hijacked by cancer.

Scientists at The Institute of Cancer Research, London, captured images of molecular machinery called RNA polymerase III in the act of decoding a gene. They used an advanced form of electron microscopy called Cryo-EM, for which the Nobel Prize in Chemistry was awarded in 2017, to zoom in and capture images of the reading mechanism in unprecedented detail.

The discovery – published in the journal Nature and portrayed on the front cover – revealed five key stages in which the RNA Polymerase III complex reshapes itself to successfully transcribe the DNA into RNA. Each of these stages could potentially become the target of new cancer drugs.

Dr Alessandro Vannini said:

“Now we know how the components of this crucial molecular mechanism fit together, we may be able to design drugs that turn the system on or off – and these could offer a whole new way of treating cancer.”

The work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Cancer Research UK and the Wellcome Trust.

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January 2018

Gene therapy could improve breast reconstruction after cancer treatment

3D print of HIV. The virus surface (yellow) is covered with proteins (purple) that enable the virus to enter and infect human cells. Source: Flickr. Licence: CC BY 2.0.

Our scientists showed that genetically reprogramming healthy cells could protect these cells from the harmful side-effects of radiotherapy after treatment for breast cancer.

In the future, this process could protect healthy tissue transplanted during cancer surgery – improving outcomes for breast reconstruction surgery in women with breast cancer by avoiding scarring or shrinkage of the subcutaneous tissues and skin.

Scientists at The Institute of Cancer Research, London, used a virus to deliver extra copies of two different genes to rats treated with radiotherapy. The genes play roles in limiting stress from harmful particles cellular stress and scarring responses to radiotherapy.

After radiotherapy, the healthy tissues that had been treated with this gene combination shrank by just 15 per cent, compared with 70 per cent in those that had not received the treatment.

Study leader Professor Kevin Harrington said:

“Some women who need radiotherapy after a mastectomy have to wait for six months before they can have breast reconstruction surgery, to allow time for side-effects to settle. This delay can have negative effects on well-being and body image.

“We hope this new viral gene therapy could protect healthy tissue transplanted during cancer surgery,bringing forward the subsequent operation to allowing immediate reconstruction of the breast at the time of removal of the cancer.”

The research, published in Science Translational Medicine, was largely funded by the Wellcome Trust.

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February 2018

Uncovering a key cell death regulation pathway

Our researchers have gained new insights into how the death of cells is controlled, opening up potential new approaches to treating cancer.

Dying cancer cells can release communication signals that trigger responses like death or repair. One of these messengers, called tumour necrosis factor (TNF), signals through several different routes, including through a protein called RIPK1, which our researchers are interested in as it drives tissue homeostasis, immunogenic cell death and tumour immune surveillance.

In this study, our researchers mutated an Inhibitor of APoptosis (IAP) protein in cells and mice to find out if it had an effect on RIPK1’s ability to kill cells. They found that when IAPs attached a protein group to RIPK1 – in a process called ubiquitylation – RIPK1 is inactivated and is itself marked for destruction within the cell.

The findings help scientists to understand how cancer cells can become resistant to pressures that would normally trigger cell death.

Study leader Professor Pascal Meier said:

“Our study gives important new insights into how cell death is regulated. Better understanding of these kinds of checkpoints could lead to new approaches to treating cancers.”

The research, published in the journal Molecular Cell, was funded by Breast Cancer Now, the Medical Research Council (MRC) and Komen Promise.

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February 2018

Lab-grown ‘mini tumours’ could personalise cancer treatment

Image taken from the Tumour Profiling Unit. Credit: Jan Chlebik for the ICR

Testing cancer drugs on miniature replicas of a patient’s tumour could help doctors tell in advance which treatments will work, a major study found.

Scientists at The Institute of Cancer Research, London, found that growing ‘mini tumours’ from biopsy samples could give incredibly detailed information about how tumours respond to drugs.

Use of the ‘mini tumours’ revealed patterns of gene activity, mutation and evolution – and predicted whether a drug would work between 88 and 100 per cent of the time.

In future, each patient could have mini tumours grown up and tested for drug sensitivity before starting treatment – helping to end reliance on trial and error.

The research, published in the prestigious journal Science, involved 110 patients with bowel and other digestive system cancers, but could be applied to other cancer types too.

Study leader Dr Nicola Valeri said: “We found that recreating patients’ tumours in the laboratory gave us an extremely promising way to predict if a drug would work. We need to evaluate the technique in larger studies, but it has the potential to help deliver truly personalised treatment to patients.”

The work was supported by the NIHR Biomedical Research Centre at The Royal Marsden and the ICR, and Cancer Research UK.

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April 2018

Lung cancer drug shows promise for breast cancer patients

Video: Dr Ilirjana Bajrami and Professor Nick Turner talk about the promise for using a lung cancer drug to treat a certain type of breast cancer.

Scientists at the ICR found that a drug called crizotinib, currently used to treat lung cancer, could be used as a new targeted therapy for breast cancer patients. They showed that the drug can kill breast cancer cells which have a particular genetic defect in the protein that normally acts as ‘velcro’ between cells, called E-cadherin.

The researchers used an approach called ‘synthetic lethality’, which targets tumour cells’ weakness to kill them. By blocking the function of one of two genes that the cancer cell relies on to survive, if the other gene is defective the cancer cell will die.

Our researchers tested 80 drugs for a synthetic lethal effect on breast cancer cells with E-cadherin mutations. They found that crizotinib – which inhibits a structure on the cell surface known as ROS1 – had a powerful cell-killing effect.

Study leader Professor Chris Lord said: “These are hugely promising laboratory findings and we’re very keen to learn whether this class of drug really works as a treatment for women with breast cancer.”

The ICR and The Royal Marsden are now launching a major clinical trial of crizotinib in patients with E-cadherin-defective advanced lobular breast cancer.

This study, published in Cancer Discovery, was funded by Breast Cancer Now.

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April 2018

80 potential lines of attack against prostate cancer uncovered

Prostate cancer cells. Credit: Mateus Crespo, Ana Ferreira, Daniel Nava Rodrigues and Johann de Bono

In April this year, scientists at the ICR identified 80 molecular weaknesses in prostate cancer that could be targeted by drugs. Researchers, led by Professor Ros Eeles, used Big Data techniques to analyse the tumour genetics of nearly a thousand patients with prostate cancer in what was the largest and most comprehensive study of its kind.

Around a quarter of the gene mutations identified involve the targets of existing drugs that are either licensed or in clinical trials – suggesting that these could offer promise for further study as new approaches to treatment.

The research also established a timeline of genetic changes in prostate cancer which could help predict the way prostate cancer evolves in individual patients, potentially allowing treatment to be adapted to combat drug resistance.

Professor Ros Eeles, Professor of Oncogenetics at the ICR, said:

“One of the challenges we face in cancer research is the complexity of the disease and the sheer number of ways we could potentially treat it – but our study will help focus our efforts on the areas that offer most promise for patient benefit.”

The study was published in the journal Nature Genetics and was largely funded by Cancer Research UK.

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April 2018

Genetic testing targets chemotherapy for aggressive breast cancer

Breast cancer cells stained for DNA (red), NFkB (green), and a reactive oxygen species probe (blue). Credit: Julia Sero / the ICR, 2011

Women with an aggressive form of breast cancer who have faults in their BRCA genes do much better on chemotherapy drug carboplatin than standard treatment, a major clinical trial found.

Researchers at the ICR led a clinical trial comparing the effectiveness of docetaxel with carboplatin – a drug co-discovered at the ICR – in women with advanced triple-negative breast cancer.

Among women who also had BRCA gene faults, those who received carboplatin were twice as likely to respond to therapy as those given the standard treatment docetaxel.

Our researchers had predicted that carboplatin would be more effective for this patient group because it works by damaging tumour DNA – and BRCA mutations impair the ability of cancer cells to repair such damage.

The trial results, published in Nature Medicine, could lead to women with triple-negative breast cancer to be considered for BRCA testing – so the best available treatment can be selected for them.

Study co-leader Professor Andrew Tutt said:

“This was a great example of using personalised genetics to repurpose a chemotherapy drug into a targeted treatment, and I am keen for these findings to be brought into the clinic as soon as possible.”

The study was funded by Breast Cancer Now and Cancer Research UK.

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May 2018

Tumour ‘diaries’ predict cancer’s future growth

Scientists at The Institute of Cancer Research, London, developed a complex mathematical model that uses a snapshot of tumours’ genetic code to reach back in time, revealing its evolutionary history.

Our researchers used the model to develop a method that predicts how individual cancers will evolve in the future. In the study, published in Nature Genetics, the team applied their model to genetic samples from a variety of cancer types – including breast, colon and lung cancers.

By analysing the pattern of mutations in the DNA of tumour cells, the researchers were able to unravel key features about the changing genetic make-up of the cancer in the past and use this to learn the rules of evolution for specific tumours, forecasting how they will change in the future. The model has potential to allow for personalised projections about the future growth of individual cancers.

Study co-leader Dr Andrea Sottoriva said:

“In the future, we hope tools like this one will enable doctors to predict the evolutionary trajectory of cancer in individual patients and change and adapt therapy according to their cancer’s next step.”

This study was funded by the Wellcome Trust and Cancer Research UK.

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June 2018

Gene testing could identify men with prostate cancer who may benefit from immunotherapy

Image: Immunotherapy - Oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red). Credit: NIH Image gallery via Flickr.

An international study involving ICR researchers has identified a pattern of genetic changes that could pick out men with advanced prostate cancer who are likely to benefit from immunotherapy.

Researchers analysed tumour DNA from 360 men with advanced prostate cancer and found that the tumours of 7 per cent of these men were missing both copies of a gene called CDK12.

Tumour DNA without CDK12 produced more immune cells and proteins that flag tumour cells to the immune system – suggesting they could respond well to immunotherapy.

In a small pilot study, two out of four men with advanced prostate cancer whose tumours had CDK12-linked genetic changes responded remarkably well to the immunotherapy drug pembrolizumab.

The study, published in the journal Cell, was led at the ICR by Professor Johann de Bono, he said:

“Immunotherapy works for a small proportion of men with advanced prostate cancer – but when it works, it really works. Our study has revealed a distinct group of men whose tumours have genetic changes that make them likely to respond. In the future, a genetic test could help pick out these men so they can be considered for immunotherapy.”

The study was supported by funders including the Prostate Cancer Foundation and Stand Up to Cancer.

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July 2018

Teamwork between cells fuels aggressive childhood brain tumour

A single image of a human brain using a magnetic resonance imaging (MRI) machine

Scientists at The Institute of Cancer Research, London, led research that discovered how cells from an aggressive type of childhood brain cancer work together to infiltrate the brain.

Diffuse intrinsic pontine glioma (DIPG) is incredibly difficult to treat – nearly all children with this type of cancer die within two years. Our findings could ultimately lead to much-needed new treatments.

The ICR scientists found that DIPGs are made up of more than one type of cell – and that cancer cells work with neighbouring cells to leave the original tumour and travel into the brain. The research showed how complex the disease is, and why a multi-pronged attack is likely to be necessary for treatment.

The study was led by Professor Chris Jones, Professor of Childhood Brain Tumour Biology at the ICR. He said:

“The idea that the cells are working together to make the disease grow and become aggressive is new and surprising.

“Crucially, this gives us hope that we can develop new treatments.”

The research was funded by Cancer Research UK with support from Abbie’s Army and the DIPG Collaborative, and was published in Nature Medicine.

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