New cancer drug targets accelerate path to precision medicine

In one of the largest studies of its kind, researchers used CRISPR technology to disrupt every gene in over 300 cancer models from 30 cancer types and discover thousands of key genes essential for cancer’s survival. The team, from the Wellcome Sanger Institute and Open Targets, then developed a new system to prioritise and rank 600 drug targets that show the most promise for development into treatments.

The results, published today (10 April) in Nature, accelerate the development of targeted cancer treatments and bring researchers one step closer to producing the Cancer Dependency Map, a detailed rulebook of precision cancer treatments to help more patients receive effective therapies.

Every two minutes someone in the UK is diagnosed with cancer, and one in two people will develop cancer at some point in their lives. Surgery, chemotherapy and radiotherapy are commonly used to treat cancer, however while they can be effective at killing the cancer cells, some patients don’t respond to treatment and healthy tissue can be damaged, leading to unwanted toxic side effects for patients.

Scientists and pharmaceutical companies are exploring new targeted therapies that selectively kill cancer cells, leaving healthy tissue unharmed. Currently, producing new effective treatments is very difficult; it costs approximately $1-2 billion to develop a single drug, but around 90 per cent of drugs fail during development. Therefore, selecting a good drug target at the beginning of the process can be seen as the most important part of drug discovery.

Researchers at the Wellcome Sanger Institute, GSK, EMBL-EBI, Open Targets and their collaborators have conducted one of the largest CRISPR screens of cancer genes to date, disrupting nearly 20,000 genes in over 300 cancer models from 30 cancer types to uncover which genes are critical for cancer survival. The team focused on common cancers, such as lung, colon and breast, and cancers of particular unmet clinical need, such as lung, ovarian and pancreatic, where new treatments are urgently needed.

Scientists identified several thousand key cancer genes and developed a prioritisation system to narrow down the list to approximately 600 genes that showed the most promise for drug development.

A top-scoring target present in multiple different cancer types was Werner syndrome RecQ helicase (WRN). The team found that cancer cells with a faulty DNA repair pathway, known as microsatellite unstable cancers, require WRN for survival. Microsatellite instability occurs in many different cancer types, including 15% of colon and 28% of stomach cancers*. The new identification of WRN as a promising drug target offers an exciting opportunity to develop the first cancer treatments to target WRN**.

Dr Kosuke Yusa, co-lead author previously from the Wellcome Sanger Institute and Open Targets, now based at the Institute of Frontier Life and Medical Sciences, Kyoto University, said: “CRISPR is an incredibly powerful tool that enables us to do science at a scale and with a precision that we couldn’t do five years ago. With CRISPR we have discovered a very exciting opportunity to develop new drugs targeting cancers.”

Dr Francesco Iorio, co-first author from the Wellcome Sanger Institute and Open Targets, said: “To give a new drug the best chance of succeeding in the very final phases of clinical trials, it is crucial to select the best and most promising drug target at the beginning of the drug development process. For the first time, in a data-driven way, we provide guidance at a genome-scale on which new therapeutic targets should be put forward for the development of new anti-cancer drugs.”

The collaboration between researchers at Sanger, EMBL-EBI and GSK, the Open Targets partners, bolster the translation of these research results into new treatments.

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.

Dr Mathew Garnett, co-lead author from the Wellcome Sanger Institute and Open Targets, said: “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. 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.”

Dr Fiona Behan, co-first author from the Wellcome Sanger Institute and Open Targets, said: “With the Cancer Dependency Map, I really hope to revolutionise treatment for patients. I didn’t get in this game to generate long lists of priority targets, I want to make a difference in a patient’s life. Even a handful of new, more effective anti-cancer drugs in the clinic or an improvement in the drug development process as a result of this research would benefit an enormous number of patients.”

Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “What makes this research so powerful, is the scale. CRISPR provides a unique tool to accelerate discovery of oncology drug targets, and this study is a salient leap in a positive direction.

“But we should remember that studying cells in the lab doesn’t always reflect the complexities of cancer in the human body and so will not necessarily reflect how someone will respond to a drug. This work provides some excellent starting points and the next steps will be a thorough analysis of the genes that have been identified as weaknesses in this study, to determine if they will one day lead to the development of new treatments for patients.”

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Notes to Editors:

*I Cortes-Ciriano et al. (2017) A molecular portrait of microsatellite instability across multiple cancers. Nature Communications. DOI: 10.1038/ncomms15180

**In a complementary paper also published in Nature, a team led by researchers from the Broad Institute of MIT and Harvard, and the Dana-Farber Cancer Institute in the United States conducting similar dependency mapping experiments also discovered a strong dependency on WRN in microsatellite unstable cancers, lending further support to WRN as a promising drug target.

***The Cancer Dependency Map at Sanger is a project with four components – drugs, models, genes and analytics – which together contribute to the production of a rulebook for the precision treatment of cancer. https://depmap.sanger.ac.uk/

Mapping the dependencies of cancers is an international effort by the Sanger Institute in the UK and the Broad Institute in the United States. Researchers aim to bridge the translational gap that exists between genomic sequencing and providing precision medicine to the many cancer patients. Genes that are critical to a cancer’s survival represent dependencies: vulnerabilities that might serve as targets for designing new therapies or repurposing existing ones. Mapping these dependencies is essential to making precision cancer medicine a reality.

Publication:

Fiona Behan et al. (2019) Prioritisation of cancer therapeutic targets using CRISPR-Cas9 screens. Nature. DOI: 10.1038/s41586-019-1103-9

Funding:

This study was supported by Open Targets (OTAR015), SU2C (SU2C0-AACR-DT1213), Wellcome and others. Dr Mathew Garnett is a CRUK funded researcher. For the full list of funders please refer to the publication.

Selected websites:

Open Targets

Open Targets is a pioneering public-private collaboration that aims to transform drug discovery by systematically improving the identification and prioritisation of drug targets and improving the success rate for developing new medicines. The consortium is a unique, pre-competitive partnership between companies and not-for-profit research institutes. The partners are GSK, Biogen, Takeda, Celgene, Sanofi, the Wellcome Sanger Institute and the EMBL’s European Bioinformatics Institute (EMBL-EBI). Open Targets combines the skills, knowledge and technologies of its partner organisations, offering a critical mass of expertise that does not exist in any single institution. Large-scale genomic experiments (Sanger Institute) and computational techniques (EMBL-EBI) developed in the public domain are blended with formal pharmaceutical R&D approaches to identify causal links between targets, pathways and diseases. This enables the partners to systematically identify drug targets, and prioritise them for further exploration. Find more at https://www.opentargets.org/ or follow @targetvalidate

About Kyoto University

Kyoto University is one of Japan and Asia’s premier research institutions, founded in 1897 and responsible for producing numerous Nobel laureates and winners of other prestigious international prizes. A broad curriculum across the arts and sciences at both undergraduate and graduate levels is complemented by numerous research centers, as well as facilities and offices around Japan and the world. For more information please see: http://www.kyoto-u.ac.jp/en

About GSK

GSK – a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. We have 3 global businesses that research, develop and manufacture innovative medicines, vaccines and consumer healthcare products. We aim to bring differentiated, high-quality and needed healthcare products to as many people as possible using our scientific and technical know-how.

In 2014 GSK became one of the founding members of Open Targets to systematically improve the identification and prioritisation of drug targets that could lead to safe and effective medicines. For further information please visit http://www.gsk.com

About Cancer Research UK

• Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research.
• Cancer Research UK’s pioneering work into the prevention, diagnosis and treatment of cancer has helped save millions of lives.
• Cancer Research UK receives no government funding for its life-saving research. Every step it makes towards beating cancer relies on vital donations from the public.
• Cancer Research UK has been at the heart of the progress that has already seen survival in the UK double in the last forty years.
• Today, 2 in 4 people survive their cancer for at least 10 years. Cancer Research UK’s ambition is to accelerate progress so that by 2034, 3 in 4 people will survive their cancer for at least 10 years.
• Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses.
• Together with its partners and supporters, Cancer Research UK’s vision is to bring forward the day when all cancers are cured.
• Cancer Research UK has extensive expertise in drug discovery and development as established through the charity’s Therapeutic Discovery Laboratories and Centre for Drug Development. The organisation also has access to large scale clinical trial capabilities through the Experimental Cancer Medicine Centre (ECMC) network.

For further information about Cancer Research UK’s work or to find out how to support the charity, please call 0300 123 1022 or visit http://www.cancerresearchuk.org. Follow us on Twitter and Facebook.

The Wellcome Sanger Institute
T

he Sanger is one of the world’s leading genome and biodata institutes. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease and to understand life on Earth. Find out more at http://www.sanger.ac.uk or follow @sangerinstitute

About Wellcome

Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation.