Open Targets hits cancer bullseye

Scientists based at the Wellcome Genome Campus in Hinxton have used CRISPR gene editing technology to identify 600 cancer-enabling genes which are essential for the disease to develop.

The study, one of the largest CRISPR screens of cancer genes to date, was published to global acclaim last week in the journal Nature. It is the first major project by Open Targets, a collaboration between Biogen, Celgene, the European Bioinformatics Institute, GSK, Sanofi, Takeda and the Wellcome Sanger Institute, which is based on the campus.

Open Targets is a pre-competitive, public-private partnership that uses human genetics and genomics data to systemically identify and prioritise drug targets.

“It’s quite a unique model,” says Oana Stroe, communications officer at the European Bioinformatics Institute. “The aim is to collaborate and share expertise in order to make the drug discovery process smoother and more effective.”

Researchers working across the participating organisations disrupted every gene in more than 300 cancer models from 30 cancer types, resulting in the identification of 600 new targets which need to be knocked out or disabled to cancel the malignant entity.

The datasets produced in this new study lay the foundations for producing the Cancer Dependency Map, a detailed rulebook for the precision treatment of cancer.

“The Cancer Dependency Map is a huge effort to identify all the weaknesses that exist in different cancers so we can use this information to empower the next generation of precision cancer treatments,” said Dr Mathew Garnett, co-lead author from the Wellcome Sanger Institute and Open Targets.

“Ultimately we hope this impacts on the way we treat patients, so many more patients get effective therapies. In the meantime, this tool will be freely available for scientists across the world to understand what makes a cancer a cancer, and how we might target different types of cancers much more effectively than we do today.”

“Open Targets was founded five years ago by GSK, Wellcome Sanger and the European Bioinformatics Institute,” says the organisation’s director, Ian Dunham. “We initiated this project as one of our first four years ago and gradually brought new partners in.

“In cancer one of the questions is how do you find combinations of drugs – single drugs might find resistance, so instead of a single CRISPR guide, what about combinations used with another drug? This is the first big project we’ve published using those kinds of approaches – there’s more on the way that need confirmation.”

Praise for the publication of the research was immediate. Eric Rhodes, of licensing company ERS Genomics – until 2016 CTO at Horizon Discovery – told the Cambridge Independent: “There are 600 genes identified from which treatments could be developed – they’re cancer-dependent, so one or more of these genes is required for a cancer to survive.

“It’s 600 shots on goal. Some genes will have a drug treatment in place, but for others they’ll try and design drugs, test their effectiveness and work up to doing tests in humans.

“They’ve jump-started the traditional model by a couple of years.”

Ben Cross, head of functional genomic screening at gene editing specialist Horizon Discovery, was also impressed.

“I became aware of the study quite recently,” he said. “It’s very close to what we do but they are taking it to a new level. The heroic thing about this study is that it’s taken a very unbiased approach to cancer types, histologies and patient backgrounds to focus on weaknesses in the genes. Where such huge data sets were usually very noisy, they’re now very clean.

“The most exciting thing is the scale of it and the level of integration they’ve conducted with other types of data, including novel gene knockout technology, but 600 new genes... that’s already a huge potential amount of new detail.

“It’s an incredible analysis to do, though the principal of synthetic lethality is well trodden. It’s the process of identifying potential treatments for cancer by finding what cancer tissues depend on. It’s very important as chemotherapy involves pain and, if we can avoid it, it’s the best way of trying to eliminate cancer. What’s new is the scale. This study says ‘forget what we knew before and let’s throw whatever we can at this’ and these 600 genes will provide many new options for drug development. The ability of Wellcome Sanger to do things at scale is what’s so exciting.”

It will still take five to seven years before new drugs go on sale, but the discovery process has now been significantly shortened.

“We’re at the beginning of this process,” says Dr Dunham, “and the hope is that it will result in better targets, better drugs. But you still have to make the drug, then once you have the drug that kills cancer cells you have to test it through clinical trials – you can’t speed up that part of the development cycle.”

“It’s also relevant to highlight there are two major components in the Open Targets partnership,” says Dr Denise Carvalho-Silva, scientific outreach lead at the European Bioinformatics Institute.

“The first is data generation through wet lab experimental projects: the Nature paper being the first set of experimental data from Open Targets to be published. The second is data integration through bioinformatics projects: Open Targets Platform and Open Targets Genetics are some of the tools we’ve developed.”

“All bioinformatics resources and new data we create will be freely available and accessible to everyone.”