Cambridge-led study clears way to precision cancer medicines
Cambridge genomics sleuths have mapped a path to precision medicine for cancer sufferers via a technology triage that prioritised and ranked 600 drug targets that show most promise for development into treatments. The breakthrough could revolutionise cancer drug discovery.
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 the 600 optimum drug targets.
The results, published today 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 – but 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.
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. So 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 conducted the CRISPR screen of cancer genes. 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 per cent of colon and 28 per cent 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 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.”
Dr Mathew Garnett, co-lead author from the Wellcome Sanger Institute and Open Targets, added: “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.”