̽��ֱ�� of Cambridge - Carlos Caldas

Four-stranded DNA structures found to play role in breast cancer

cjb250 — Mon, 03 Aug 2020 15:01:09 +0000

In 1953, Cambridge researchers Francis Crick and James Watson co-authored a study published in the journal Nature which showed that DNA in our cells has an intertwined, ‘double helix’ structure. Sixty years later, a team led by Professor Sir Shankar Balasubramanian and Professor Steve Jackson, also at Cambridge, found that an unusual four-stranded configuration of DNA can occur across the human genome in living cells.

These structures form in regions of DNA that are rich in one of its building blocks, guanine (G), when a single strand of the double-stranded DNA loops out and doubles back on itself, forming a four-stranded ‘handle’ in the genome. As a result, these structures are called G-quadruplexes.

Professor Balasubramanian and colleagues have previously developed sequencing technologies and approaches capable of detecting G-quadruplexes in DNA and in chromatin (a substance comprised of DNA and proteins). They have previously shown that G-quadruplexes play a role in transcription, a key step in reading the genetic code and creating proteins from DNA. Crucially, their work also showed that G-quadruplexes are more likely to occur in genes of cells that are rapidly dividing, such as cancer cells.

Now, for the first time, the team has discovered where G-quadruplexes form in preserved tumour tissue/biopsies of breast cancer. Details of their study are published today in the journal Nature Genetics.

̽��ֱ��Cambridge team led by Professor Balasubramanian and Professor Caldas used their quantitative sequencing technology to study G-quadruplex DNA structures in 22 model tumours. These models had been generated by taking biopsies from patients at Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospital NHS Foundation Trust, then transplanting and growing the tumours in mice.

During the process of DNA replication and cell division that occurs in cancer, large regions of the genome can be erroneously duplicated several times leading to so-called copy number aberrations (CNAs). ̽��ֱ��researchers found that G-quadruplexes are prevalent within these CNAs, particularly within genes and genetic regions that play an active role in transcription and hence in driving the tumour’s growth.

Professor Balasubramanian said: “We’re all familiar with the idea of DNA’s two-stranded, double helix structure, but over the past decade it’s become increasingly clear that DNA can also exist in four-stranded structures and that these play an important role in human biology. They are found in particularly high levels in cells that are rapidly dividing, such as cancer cells. This study is the first time that we’ve found them in breast cancer cells.”

“ ̽��ֱ��abundance and location of G-quadruplexes in these biopsies gives us a clue to their importance in cancer biology and to the heterogeneity of these breast cancers,” added Dr Robert Hänsel-Hertsch who is now at the Center for Molecular Medicine Cologne, ̽��ֱ�� of Cologne, and is first author on the publication.

“Importantly, it highlights another potential weak spot that we might use against the breast tumour to develop better treatments for our patients.”

There are thought to be at least 11 subtypes of breast cancer, and the team found that each has a different pattern – or ‘landscape’ – of G-quadruplexes that is unique to the transcriptional programmes driving that particular subtype.

Professor Carlos Caldas from the Cancer Research UK Cambridge Institute, said: “While we often think of breast cancer as one disease, there are actually at least 11 known subtypes, each of which may respond in different ways to different drugs.

“Identifying a tumour’s particular pattern of G-quadruplexes could help us pinpoint a woman’s breast cancer subtype, enabling us to offer her a more personalised, targeted treatment.”

By targeting the G-quadruplexes with synthetic molecules, it may be possible to prevent cells from replicating their DNA and so block cell division, halting the runaway cell proliferation at the root of cancer. ̽��ֱ��team identified two such molecules – one known as pyridostatin and a second compound, CX-5461, which has previously been tested in a phase I trial against BRCA2-deficient breast cancer.

̽��ֱ��research was funded by Cancer Research UK.

Reference
Hänsel-Hertsch, R et al. Landscape of G-quadruplex DNA structural regions in breast cancer. Nat Gen; 3 Aug 2020; DOI: 10.1038/s41588-020-0672-8

Four-stranded DNA structures – known as G-quadruplexes – have been shown to play a role in certain types of breast cancer for the first time, providing a potential new target for personalised medicine, say scientists at the ̽��ֱ�� of Cambridge.

We’re all familiar with the idea of DNA’s two-stranded, double helix structure, but over the past decade it’s become increasingly clear that DNA can also exist in four-stranded structures and that these play an important role in human biology

Shankar Balasubramanian

Thomas Splettstoesser

Crystal structure of parallel quadruplexes from human telomeric DNA. ̽��ֱ��DNA strand (blue) circles the bases that stack together in the center around three co-ordinated metal ions (green)

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Leading European cancer centres share guidance on making their operations ‘pandemic proof’

cjb250 — Thu, 16 Apr 2020 16:44:27 +0000

̽��ֱ��centres, which include the Cancer Research UK Cambridge Cancer Centre, form an alliance known as Cancer Core Europe (CCE), and together represent around 60,000 newly diagnosed cancer patients each year and conduct more than 1,500 clinical trials.

In a Perspective published in Nature Medicine, CCE researchers describe how their centres have been forced by the current pandemic to drastically revise and reorganise their patient care and scientific research, while maintaining the same high quality of care.

̽��ֱ��specialist centres not only want to prevent the spread of the virus in general, but also to protect patients with cancer whose disease and treatment make them especially vulnerable to complications if infected.

“COVID-19 has created a unique challenge: how to adjust cancer management to minimise the disruption caused to cancer care by the pandemic,” said Professor Carlos Caldas, co-lead author of the article, member of the senior management team of the Cancer Research UK Cambridge Centre, and Group Leader at the Cancer Research UK Cambridge Institute.

“Our medical staff across all disciplines have been truly amazing at very quickly producing COVID-19-adjusted treatment guidelines.”

̽��ֱ��researchers have identified several factors that medical institutions need to consider to ensure continuity in cancer care as the COVID-19 pandemic unfolds. These include:

Clinical activities
Given the high transmissibility rate of SARS-Cov2, it is the responsibility of all health care professionals to make sure patients are not exposed to COVID-19. For CCE centres, this means that face-to-face consultations are now, whenever possible, taking place via web consulting or by telephone calls, and non-urgent appointments are postponed.
Adaptation of standard-of-care treatment regimens
Across all centres, standard-of-care treatment regimens have been adapted to minimize the number of hospital visits and hospitalizations, and to prevent complications of COVID-19 caused by anticancer treatments.
Patient information and psychosocial care
Addressing patients’ concerns relating to their treatment and how it may be affected by COVID-19 poses a challenge to CCE centres and has required urgent attention.
Support of qualified personnel
In order to ensure the continuity of cancer care, the presence of sufficient qualified personnel to treat cancer patients is essential. This involves the whole chain of hospital caregivers, from the operating theatre, to the ward, day clinic, and intensive care unit (ICU). Every CCE has faced a similar problem: the absence of a rapid diagnostic system for COVID-19 for caregivers. This frequently leads to unnecessary self-isolation of health professionals, further reducing the health workforce in a time when demand is peaking.
Capacity of cancer care facilities
In many hospitals, the COVID-19 pandemic is a major stress test for the capacity of the various treatment or support units: radiation, medical oncology, imaging, surgery and ICUs. With increasing severity of the pandemic, health care systems will become overwhelmed and prioritization will be necessary. To prepare for this, CCE centres have established decision rules to categorize and prioritize patients for anticancer therapies or surgery.
Research activities
CCE centres have large research facilities and together employ thousands of preclinical scientists. One of the first measures taken was to downscale these preclinical research activities to a minimum in accordance with social distancing guidelines and the ‘lockdown’ local policy. Clinically trained scientists and research fellows are frequently going back to clinical work to support their healthcare system.

̽��ֱ��authors acknowledge that the current crisis will have major ramifications to the progress of cancer research. However, public health measures in place to curtail the COVID-19 pandemic have to be prioritized at the moment, and the damage to the scientific enterprise will be repairable in time if safeguards and resources are put in place.

̽��ֱ��team outline a set of practical measures that have been implemented in their respective centres and could be considered by other medical centres. These range from instructing patients where possible not to visit the hospital if they have possible symptoms of COVID-19 to reducing preclinical research activities to a bare minimum, and from informing patients about a possibly increased risk associated with anticancer therapy during the pandemic through to considering non-surgery-based treatments, such as radiation for prostate cancer.

Professor Caldas added: “We hope that our collective experiences will help guide others and will also reassure cancer patients that we are doing everything we can to avoid compromising their care.

“This COVID-19 crisis is making us rethink care, and some of the changes might in the long run have positive effects, for example minimising hospital visits and face-to-face consultations or delivering care using telemedicine.”

̽��ֱ��Cancer Core Europe (CCE) alliance of seven leading European cancer centres was founded in 2014 to accelerate the development of innovative cancer therapies through close collaboration in translational and clinical research. Its seven member centres collectively treat approximately 350,000 patients annually.

̽��ֱ��Cancer Research UK Cambridge Centre acknowledges funding from Cancer Research UK, the National Institute for Health Research Cambridge Biomedical Research Centre, and ̽��ֱ��Mark Foundation for Cancer Research. Its clinical cancer services are provided by Cambridge ̽��ֱ�� Hospitals (CUH) and Royal Papworth Hospital.

Reference
Caring for patients with cancer in the COVID-19 era. Nat Med; 16 Apr 202; DOI: 10.1038/s41591-020-0874-8

Seven of Europe’s leading cancer centres have today published a report detailing how they have organized their healthcare systems at an unprecedented scale and pace to make their operations ‘pandemic proof’ during the COVID-19 pandemic.

COVID-19 has created a unique challenge: how to adjust cancer management to minimise the disruption caused to cancer care by the pandemic

Carlos Caldas

CRUK Cambridge Institute

Yes

Zooming in on breast cancer reveals how mutations shape the tumour landscape

Anonymous — Mon, 17 Feb 2020 15:40:21 +0000

An international team of scientists, brought together by a £20 million Grand Challenge award from Cancer Research UK, has developed intricate maps of breast tumour samples, with a resolution smaller than a single cell.

These maps show how the complex cancer landscape, made up of cancer cells, immune cells and connective tissue, varies between and within tumours, depending on their genetic makeup.

This technique could one day provide doctors with an unparalleled wealth of information about each patient’s tumour upon diagnosis, allowing them to match each patient with the best course of treatment for them.

In the future, it could also be used to analyse tumours during treatment, allowing doctors to see in unprecedented detail how tumours are responding to drugs or radiotherapy. They could then modify treatments accordingly, to give each patient the best chance of beating the disease.

Dr Raza Ali, lead author of the study and junior group leader at the Cancer Research UK Cambridge Institute, said: “At the moment, doctors only look for a few key markers to understand what type of breast cancer someone has. But as we enter an era of personalised medicine, the more information we have about a patient’s tumour, the more targeted and effective we can make their treatment.”

̽��ֱ��researchers studied 483 different tumour samples, collected as part of the Cancer Research UK funded METABRIC study, a project that has already revolutionised our understanding of the disease by revealing that there are at least 11 different subtypes of breast cancer.

̽��ֱ��team looked within the samples for the presence of 37 key proteins, indicative of the characteristics and behaviour of cancer cells. Using a technique called imaging mass cytometry, they produced detailed images, which revealed precisely how each of the 37 proteins were distributed across the tumour.

̽��ֱ��researchers then combined this information with vast amounts of genetic data from each patient’s sample to further enhance the image resolution. This is the first time imaging mass cytometry has been paired with genomic data.

These tumour ‘blueprints’ expose the distribution of different types of cells, their individual characteristics and the interactions between them.

By matching these pictures of tumours to clinical information from each patient, the team also found that the technique could be used to predict how someone’s cancer might progress and respond to different treatments.

Professor Carlos Caldas, co-author of the study from the Cancer Research UK Cambridge Institute, said: “We’ve shown that the effects of mutations in cancer are far more wide-ranging than first thought.

“They affect how cancer cells interact with their neighbours and other types of cell, influencing the entire structure of the tumour.”

̽��ֱ��research was funded by Cancer Research UK’s Grand Challenge initiative. By providing international, multidisciplinary teams with £20 million grants, this initiative aims to solve the biggest challenges in cancer.

Dr David Scott, director of Grand Challenge at Cancer Research UK said: “This team is making incredible advances, helping us to peer into a future when breast cancer treatments are truly personalised.

“There’s still a long way to go before this technology reaches patients, but with further research and clinical trials, we hope to unlock its powerful potential.”

Reference:
H. Raza Ali et al. 'Imaging mass cytometry and multi-platform genomics define the phenogenomic landscape of breast cancer.' Nature Cancer (2020). DOI: 10.1038/s43018-020-0026-6

Adapated from a Cancer Research UK press release.

Scientists have created one of the most detailed maps of breast cancer ever achieved, revealing how genetic changes shape the physical tumour landscape, according to research funded published in Nature Cancer.

We’ve shown that the effects of mutations in cancer are far more wide-ranging than first thought

Carlos Caldas

H. Raza Ali

Molecular map of a breast tumour

Yes

Molecular patterns could better predict breast cancer recurrence

Anonymous — Wed, 13 Mar 2019 18:18:50 +0000

In the first study of its kind, scientists at the Cancer Research UK Cambridge Institute at the ̽��ֱ�� of Cambridge, in collaboration with Professor Christina Curtis at Stanford ̽��ֱ��, examined the patterns of genetic changes within tumours from nearly 2,000 women with breast cancer and followed their progress over 20 years – including whether their cancer returned. They used this information to create a statistical tool that can better predict if, and when a women’s breast cancer could come back.

While the genetic analyses used in the study are too detailed for everyday use, the team are now working on a routine test that could one day help doctors offer women a more accurate prediction of if, and when, their disease may return. Although not available to patients yet, this means that in the future, treatments and follow-up can be tailored, improving women’s chances of survival.

Professor Carlos Caldas, lead researcher at the Institute, said: “Treatments for breast cancer have improved dramatically in recent years, but unfortunately for some women, their breast cancer returns and spreads, becoming incurable. For some, this can be many years later – but it’s been impossible to accurately predict who is at risk of recurrence and who is all clear.

“In this study, we’ve delved deeper into breast cancer molecular subtypes, so we can more accurately identify who might be at risk of relapsing and uncover new ways of treating them.”

Previous results from this group of researchers had already revealed that breast cancer isn’t just one disease, but instead could be classified into one of eleven different molecular subgroups.

̽��ֱ��latest findings highlight how these molecular subtypes have distinct clinical ‘trajectories’, which can’t be predicted by looking at commonly used characteristics (such as size, stage, oestrogen receptor (ER), or Her2 status) alone.

These clinical trajectories vary considerably, even between tumours that seem similar. For example, the team found, among women with a form of the disease called triple-negative breast cancer, there was a distinct subgroup whose outlook is initially poor, but for whom the disease is unlikely to come back in those who survived 5 years.

They also identified subgroups of women with oestrogen receptor-positive (ER+) tumours, who were at a higher risk of their cancer coming back up to 20 years after they were first diagnosed. Around 12,300 women in the UK could belong to one of these late relapse subgroups and therefore might benefit from longer courses of treatments such as tamoxifen, or more frequent check-ups

“We’ve shown that the molecular nature of a woman’s breast cancer determines how their disease could progress, not just for the first 5 years, but also later, even if it comes back.” said Dr Oscar Rueda, first author of the paper and senior research associate at the Cancer Research UK Cambridge Institute. “We hope that our research tool can be turned into a test doctors can easily use to guide treatment recommendations.”

̽��ֱ��model also revealed how molecular subgroups could behave very differently if a patient’s cancer returns. They commonly spread to different parts of the body and some are more aggressive than others, affecting how much time women survive for following a relapse

Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “This study provides some valuable new insights into how we might identify women whose breast cancer is likely to return.

“We’re still a way off being able to offer this type of detailed molecular testing to all women and we need more research to understand how we can tailor treatments to a patient’s individual tumour biology. But this is incredibly encouraging progress. One in seven women will get breast cancer in their lifetime in the UK, and we hope that research like this will mean that if faced with the disease, even more of our daughters and granddaughters will survive.”

In addition to developing an affordable test for future use in hospitals, Caldas’ team are also already investigating personalised treatment options for different breast cancer subtypes. ̽��ֱ��next steps will be to recruit patients onto different clinical trials depending on the molecular makeup of their tumour.

Catharine Scott, 51, from Cambridge, was diagnosed with triple negative breast cancer in 2016. She had the molecular biology of her tumour analysed as part of the Personalised Breast Cancer Programme at Addenbrooke’s Hospital, which is part of Cambridge ̽��ֱ�� Hospital NHS Foundation Trust. This programme aims to confirm whether women are receiving the best treatment for their tumour type, and if they might be eligible for a clinical trial should they relapse in the future.

Since finishing treatment, Catharine had one scare in the summer of 2018, but it was not a recurrence. She has annual check-ups and mammograms.

Catharine said: “I finished my treatment and found it very strange knowing I wouldn’t see anyone for a year. I was at the hospital every week, then every three, then suddenly that’s it. It’s quite scary and definitely a worry. I spoke to my consultant at the time and asked, ‘How likely am I to get this again?’

“They can tell you the risks and likelihood, and how things have been in the past. If they were able to make it more personalised that would be more reassuring. It would definitely be better than feeling you have to cross your fingers.

“I feel lucky to have been on the trials and I’m glad to be helping with research. Women in the past contributed to get treatment where it is today and I’m glad to be doing my bit for my daughter, for other women and for the future generations.”

Adapted from a press release from Cancer Research UK.

Reference:
Rueda, O., et al. Dynamics of breast cancer relapse reveal late recurring ER-positive genomic subgroups. Nature; 13 March 2019; DOI: 10.1038/s41586-019-1007-8

̽��ֱ��genetic and molecular make-up of individual breast tumours holds clues to how a woman’s disease could progress, including the likelihood of it coming back after treatment, and in what time frame, according to a study published in Nature.

We can more accurately identify who might be at risk of relapsing and uncover new ways of treating them

Carlos Caldas

Yes

Cambridge first UK centre to be given ‘Comprehensive Cancer Center of Excellence’

cjb250 — Tue, 13 Feb 2018 00:17:56 +0000

̽��ֱ��combination of world-leading science and cutting-edge technology in Cambridge means that patients are benefiting from new ways to spot and treat the earliest signs of cancer, more effective and kinder therapies, and treatments that are tailored to individual patients.

Cambridge receives the prestigious recognition as one of the top two cancer centres in Europe for outstanding academic research that is improving outcomes for cancer patients, alongside the Netherlands Cancer Institute.

Professor Carlos Caldas, Director of the Breast Cancer Programme and lead for European collaborations at the CRUK Cambridge Centre said: “This new and prestigious designation by the EACS is for us an enormous privilege and also a responsibility. This designation only makes us even more focused in delivering outstanding clinical care for our patients underpinned by the world-class research programmes at the ̽��ֱ�� and CRUK Cambridge Institute.”

̽��ֱ��European Academy of Cancer Sciences was created in 2009 as an independent advisory body of eminent oncologists and cancer researchers, placing science at the core of policies to sustainably reduce the death and suffering caused by cancer in Europe.

̽��ֱ��EACS designation is highly regarded because the Academy has spent several years developing a rigorous methodology for assessing how well cancer centres are doing in conducting translational research. This is the process of translating the latest scientific discoveries into clinical applications which will improve the diagnosis and treatment of cancer patients – often coined ‘from bench to bedside and back’.

“I was very impressed by [Cambridge’s] capacity to bring together so many highly motivated talented scientists and clinicians in one ambitious synergistic endeavour,” said Dr Anton Berns, who chairs the EACS committee overseeing the Designation of Excellence process. “This is the type of setting that will make a difference for cancer patients and that is precisely why they are so deserving of this prestigious title. Clearly, an example for other institutions to follow.”

̽��ֱ��Cancer Research UK Cambridge Centre is one of only two Cancer Research UK Centres that was elevated to Major Centre status in 2017, and is now the largest CRUK Cancer Centre by funding. ̽��ֱ��Centre unites more than 600 laboratory and healthcare professionals around a common mission to end death and disease caused by cancer, and holds a cancer-related grant portfolio totalling approximately £100 million a year.

̽��ֱ��Centre was first cancer centre in Europe based at a ̽��ֱ�� Hospital to be accredited by the Organisation European Cancer Institute as a Comprehensive Cancer Center in 2013.

Centre members are based in two major teaching hospitals, 28 ̽��ֱ�� Departments, nine allied institutions and four major pharmaceutical companies across the wider Cambridge area. ̽��ֱ��Centre is now organised into 12 Programmes that focus on the most common and difficult to treat cancers, as well as basic research disciplines in which the ̽��ֱ�� of Cambridge has particular expertise. Major inter-disciplinary research themes ongoing in the Centre are uniting teams of biomedical, physical and mathematical scientists who are developing approaches to detect and treat cancer as early and precisely as possible.

On receiving the formal certificate in January 2018, Professor Richard Gilbertson, the Li Ka Shing Chair of Oncology at Cambridge ̽��ֱ�� and Director of the CRUK Cambridge Centre said: “Cancer is a global scourge that will require deep integration of treatment and research if we are to defeat it for good. Centres like Cambridge ̽��ֱ�� and the Netherlands Cancer Institute are key components in this effort, where teams of the brightest clinicians and scientists work with together with patients to discover and develop new cures. This award recognises the impactful partnership between our patients and staff and their efforts to work internationally to cure cancer.”

̽��ֱ��EACS carried out the assessment of the CRUK Cambridge Centre and NKI with financial support from the ARC Foundation for Cancer Research.

̽��ֱ��Cancer Research UK Cambridge Centre has become the first UK institute to be designated a Comprehensive Cancer Center of Excellence by the European Academy of Cancer Sciences (EACS).

This new and prestigious designation by the EACS is for us an enormous privilege and also a responsibility

Carlos Caldas

Li Ka Shing Centre

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Milner Therapeutics Institute: a drug discovery ecosystem

lw355 — Wed, 28 Jun 2017 14:30:05 +0000

Professor Tony Kouzarides is the founding Director of the Milner Therapeutics Institute, which is due to open in 2018 on the Cambridge Biomedical Campus. ̽��ֱ��ecosystem he sees thriving within its walls is one in which academic researchers (“experts in the biology of diseases”) work closely with pharmaceutical companies (“who know what’s needed to get the drug to clinic”) to find new medicines. Put simply, he says, the Institute will be “a pipeline for drug discovery within an academic setting.”

While the labs are being fitted out with robotics for customised drug screening, gene-editing facilities to rewrite DNA and bioinformatics support to help scientists deal with huge datasets, the partnerships between industry and academia are already under way.

In June 2015, a research agreement was signed between the ̽��ֱ�� of Cambridge, the Wellcome Trust Sanger Institute and the Babraham Institute with three pharmaceutical companies – AstraZeneca (AZ), Astex and GSK. Since then, Pfizer, Shionogi and Elysium Pharmaceuticals have joined the Milner Therapeutics Consortium, the outreach programme of the Institute.

With this one agreement, doors opened. Dr Kathryn Chapman, Executive Manager of the Milner Therapeutics Institute, explains: “Forming the Consortium means there’s now a free exchange of potential drug molecules between pharma and academia. This sounds straightforward but, before the agreement, this could take a year because of confidentiality and material transfer contracts. Now it takes two to three weeks. It lowers barriers of engagement, it speeds up research and it can involve hundreds of molecules in one go.”

One consequence is drugs that have already been approved for use in certain diseases are now being tested for use in other diseases – a practice called repositioning or repurposing.

“An academic might have developed a brain disease model using an organoid – a mini organ in a Petri dish,” explains Kouzarides. “We can use this to test drugs that have been licensed for use in other diseases such as arthritis or cancer.”

It also means that novel therapeutic agents across the entire portfolio of drugs being developed by each of the companies can be screened at an early stage in biological assays, to see whether any are worth progressing along the drug development pipeline.

For example, one of the Consortium’s first collaborative projects is a partnership between AZ and Professor Carlos Caldas at the Cancer Research UK Cambridge Institute.

Breast cancer consists of several different genomic subtypes, which makes effective treatment challenging and prognosis variable. Some subtypes respond well to particular drugs or drug combinations whereas others are resistant. Caldas has pioneered the development of a biobank of patient-derived breast cancer cells and tissues that have greater predictive power for clinical outcome than other preclinical models (such as cancer cell lines).Carlos and AZ are now working together to test how different subtypes of breast cancer respond to different AZ compounds and compound combinations, as well as looking at potential drug-resistance mechanisms.

From 2018, the Consortium will form a major part of the Milner Therapeutics Institute, which has been made possible through a £5m donation from Dr Jonathan Milner, a former member of Kouzarides’ research group and entrepreneur. Milner and Kouzarides are two of the founders of leading Cambridge biotechnology company Abcam.

“One of the main aims of the Institute will be to develop multiple disease models to understand how drugs could work on the real disease,” explains Kouzarides. “We plan to focus on some of the most challenging diseases to start with – cancer, neurodegeneration and inflammation – but we are disease agnostic. If we have a method of testing for efficacy and a library of molecules to test, then we’ll test!”

Kouzarides’ enthusiasm for making sure the ‘Petri-dish-to-pill’ pipeline works comes from his own positive experience of a collaboration with GSK that has resulted in a leukaemia drug now being used in the clinic to treat patients.

It came about through serendipity. “GSK was developing a molecule called I-BET against an epigenetic protein. I was a consultant on the project and became aware that the molecule could be effective against mixed lineage leukaemia (MLL), the most common type of leukaemia in children under two years old. We had the cell assays and disease models in Cambridge, and we asked to test the drug. It worked and it’s now in the clinic.

“I started to wonder why this pharma–academia collaboration doesn’t happen more often. People have been talking about the translational gap between fundamental research and the clinic for years, and it’s still there. While serendipity is good – and many amazing medical innovations have come out of chance encounters – we can’t trust only to chance.

“ ̽��ֱ��world needs new medicines to be developed. It’s time-consuming and costly, and that’s why we need an ecosystem that will nurture and speed up the success.”

̽��ֱ��Milner Institute will be within the Capella building at the Cambridge Biomedical Campus, alongside the relocated Wellcome Trust/MRC Cambridge Stem Cell Institute, the Cambridge Institute of Therapeutic Immunology and Infectious Disease, and ̽��ֱ��Cambridge Centre for Haematopoiesis and Haematological Malignancies.

Tony Kouzarides is passionate about ecosystems: well-balanced communities that flourish on mutual and dynamic interactions. But the ecosystems that excite him are not made up of plants, animals and environments. They’re made up of experts.

̽��ֱ��world needs new medicines to be developed. It’s time-consuming and costly, and that’s why we need an ecosystem that will nurture and speed up the success.

Tony Kouzarides

David Anderson

Neurons

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Study provides clues to why some breast cancers are hard to beat

cjb250 — Tue, 10 May 2016 09:50:53 +0000

Researchers from the Cancer Research UK Cambridge Institute at the ̽��ֱ�� of Cambridge analysed tumour samples from the METABRIC study – which revealed breast cancer can be classified as ten different diseases – to get a deeper understanding of the genetic faults of these ten subtypes.

They found 40 mutated genes that cause breast cancer to progress. Only a fraction of these genes were previously known to be involved in breast cancer development. They also discovered that one of the more commonly mutated genes, called PIK3CA, is linked to lower chances of survival for three of the ten breast cancer subgroups. Crucially, this might help explain why drugs targeting PIK3CA work for some women but not for others.

̽��ֱ��researchers believe the results could in the future help find drugs to target these genetic faults, stopping the disease from progressing. ̽��ֱ��research could also provide vital information to help design breast cancer trials and improved tests for the disease.

̽��ֱ��findings add a more detailed layer of information to METABRIC, a major study involving 2,000 patients. METABRIC was the largest molecular profiling study looking at how patients progress after treatment for any type of cancer. It was carried out by Cancer Research UK, in collaboration with the British Columbia Cancer Agency.

Professor Carlos Caldas, lead author at the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ��METABRIC study mapped out the genetic blueprints for breast cancer. And these new results give us even more detail about which genetic faults could be linked to how different types of breast cancer develop and progress.

“ ̽��ֱ��information could in the future help design clinical trials for breast cancer patients, or give researchers more flags to look out for in liquid biopsies, a type of test used to detect genetic material in the blood that is released by dying cancer cells.”

̽��ֱ��results will be made available to the public so that other researchers can benefit from the work.

Professor Peter Johnson, Cancer Research UK’s chief clinician, said: “Our research continues to highlight just how complicated cancers are, but we are managing to solve these puzzles faster than ever. This study gives us more vital information about how breast cancer develops and why some types are more difficult to treat than others, and this information is a great resource for researchers all over the world. Research like this will help us invent new diagnostic tests to guide treatment for breast cancer patients in the future.”

Reference
Pereira et al., ̽��ֱ��somatic mutation profile of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nature Communications; 10 May 2016. DOI: 10.1038/ncomms11479

Adapted from a press release from Cancer Reserch UK.

Scientists have unearthed crucial new genetic information about how breast cancer develops and the genetic changes which can be linked to survival, according to a study published in Nature Communications today.

These new results give us even more detail about which genetic faults could be linked to how different types of breast cancer develop and progress

Carlos Caldas

Adriënne

solidarity against cancer

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Celestial bodies

cjb250 — Wed, 04 Feb 2015 14:05:52 +0000

Despite their red-brick finish, the corridors of the Institute of Astronomy can seem more like an art gallery than a research centre, so beautiful are the images of supernovae and nebulae hanging there. Dr Nic Walton passes these every day as he makes his way to his office to study the formation of the Milky Way and search for planets outside our solar system.

On the screen of Walton’s computer is what appears to be a map of stars in our Milky Way. In fact, it is something that is around 25 orders of magnitude smaller (that’s ten followed by 25 zeros).

It is an image of cells taken from a biopsy of a patient with breast cancer; the ‘stars’ are the cells’ nuclei, stained to indicate the presence of key proteins. It is the similarities between these patterns and those of astronomical images that he, together with colleagues at the Cancer Research UK (CRUK) Cambridge Institute, is exploiting in PathGrid, an interdisciplinary initiative to help automate the analysis of biopsy tissue.

“Both astronomy and cell biology deal with huge numbers: our Milky Way contains several hundred billion stars, our bodies tens of trillions of cells,” explained Walton.

PathGrid began at a cross-disciplinary meeting in Cambridge to discuss data management. Walton has been involved for many years with major international collaborations that, somewhat appropriately, amass an astronomical amount of data. But accessing data held by research teams across the globe was proving to be a challenge, with a lack of standardised protocols. Something needed to be done and Walton was part of an initiative to sort out this mess.

̽��ֱ��issue of data management in an era of ‘big data’ is not unique to astronomy. Departments across the ̽��ֱ�� – from the Clinical School to the Library – face similar issues and this meeting was intended to share ideas and approaches. It was at this meeting that Walton met James Brenton from the CRUK Cambridge Institute. They soon realised that data management was just one area where they could learn from each other: image analysis was another.

Walton and his colleagues in Astronomy capture their images using optical or near-infrared telescopes, such as the prosaically named Very Large Telescope or the recently launched Gaia satellite, the biggest camera in space with a billion pixels. These images must then be manipulated to adjust for factors including the telescope’s own ‘signature’, cosmic rays and background illumination. They are tagged with coordinates to identify their location, and their brightness is determined.

Analysing these maps is an immense, but essential, task. Poring over images of tens of thousands of stars is a laborious, time-consuming process, prone to user error, so this is where computer algorithms come in handy. Walton and colleagues run their images through object detection software, which looks for astronomical features and automatically classifies them.

“Once we start characterising the objects, looking at what’s a star, what’s a galaxy, then we start to see the really interesting bigger picture. Light is distorted by gravitational mass on its way to us, so the shapes of the galaxies, for example, can tell us about the distribution of dark matter towards them. When we start counting stars, we start to see structures, like tidal streams.”

Professor Carlos Caldas, one of Brenton’s colleagues at the CRUK Institute, and now a collaborator of Walton’s, says the problems faced by medical pathologists are very similar, if at the opposite extreme of measurements. Could the same algorithms help pathologists analyse images taken by microscopes?

When a patient presents with suspected breast cancer, a pathologist takes a core of the tumour tissue – a tiny sample, less than 1 mm in diameter. ̽��ֱ��tumour samples are arranged on a block, typically together with 200 other samples taken from different patients. Each sample needs to have its own ‘coordinates’ so that the researchers know that a particular tumour came from a particular patient.

“We then cut a slice of the 200 or so cores, mount it into a slide that is stained, and take a digital picture of this slide,” explained Caldas, “but each of these high-resolution images is a few gigabytes of data, so we quickly accumulate hundreds of terabytes of data.”

By adapting the astronomers’ image analysis software, the PathGrid collaborators are able to analyse the tumour images, for example to recognise the three types of cells in the tissue samples: cancer cells, immune cells and stromal cells. Just as object identification in astronomy reveals hidden patterns and information, so the information from the slides begins to tell researchers how the different cell types relate to each other. Staining the samples to highlight elements such as potentially important proteins could also help the researchers identify new biomarkers to aid in the diagnosis or prognosis of cancers.

Equally important will be how the data is stored so that several years down the line, as researchers find new questions to ask, they can still access and analyse any of the 15,000 different tumours and their hundred stains. “We need to know that at some point in the future we can extract sample 53, for example, or find all tumours that were positive for a particular stain,” said Caldas. “Imagine if you had a million sheets of paper and you just threw them all into a room and asked someone to find page 53. They’d have to sort through all the papers to find the right one, but if you could make it glow, you’d be able to find it more easily. This is similar to what we do, except we do this digitally.”

As well as this technology allowing oncologists to ask new questions and at a much larger scale, Caldas believes that in the future it could be used as ‘digital pathology’, aiding diagnosis and prognosis even in regions with no specialist oncologists. “You could imagine a scenario where a clinician takes a biopsy and a pathologist processes and stains the slide, takes a picture and digitally relays it. This is then analysed by one of the algorithms to say if it is a tumour, identify the tumour type and say how aggressive it will be.”

Walton makes an interesting and unexpected comparison between his and Caldas’s work: “We deal with star deaths, they deal with patient deaths.” If PathGrid is successful, this might change: while the astronomers continue to watch star deaths, their collaborators will hopefully become even better at preventing many more patient deaths from cancer.

Inset image: Left - Carlos Caldas; right - Nic Walton

Astronomy and oncology do not make obvious bedfellows, but the search for new stars and galaxies has surprising similarities with the search for cancerous cells. This has led to new ways of speeding up image analysis in cancer research.

We deal with star deaths, they deal with patient deaths

Nic Walton

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