Crick group leader Simon Boulton co-founded Artios in 2016, a spin-out from Cancer Research UK’s Commercial Partnerships, where he is now VP of Science Strategy. Artios develops cancer treatments that target DNA damage response pathways. Simon discusses how Artios was set up, their latest trial results and how to translate research from the lab into the clinic.
DNA can be damaged during cellular processes such as DNA replication, or by external agents like UV rays from the sun. To combat this, our cells have evolved first aid kits ready to repair damaged DNA, but if these go awry, mistakes can build up that can potentially lead to cancer. My lab investigates how our cells repair DNA damage, hoping to understand how these processes work, and how defect in DNA repair and be exploited for treating cancer.
It all stemmed from research into PARP inhibitors, which were found to effectively eradicate cancers mutated in the BRCA genes, which are essential for a DNA repair pathway called homologous recombination. This showed that it was possible to specifically target a weakness in cancer cells without affecting normal tissues.
As a PhD student, I discovered an error-prone DNA repair pathway that operates in the absence of the more accurate repair pathways. 20 years after this discovery, we and others found an enzyme in this pathway, called DNA polymerase theta (POLθ), which is used to repair DNA damage in many cancers. Other researchers, including Geoff Higgins in Oxford, found that POLθ inhibition can be exploited to enhance the effectiveness of radiotherapy.
Cancer Research UK’s Therapeutic Discovery Laboratories (TDL), worked on the early stages of drug discovery to translate these findings, including a second target discovered in my lab. Building on the success of PARP inhibitors, we decided to spin this out into a company. A huge challenge was pitching the concept to the investors, but we got there, and in 2016 Artios was born.
Deficiencies in DNA repair processes are widespread in cancer as they drive genome instability and ultimately tumour evolution. Many cancers become addicted to a particular DNA repair pathway (eg. POLθ), which is something unique to the cancer cell, and can be its Achilles heel. Targeting these critical DNA repair dependencies offers the possibility of eliminating the cancer without compromising normal cells.
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Artios reported a 50% overall response rate in their STELLA trial for a potential new drug, called an ATR inhibitor, which targets the DNA damage response. The patients taking part had late-stage cancers that had often spread to other sites in the body. Many of these patients had failed numerous existing approved therapies and had no other option. Remarkably, the ATR inhibitor, when used in combination with a chemotherapeutic drug called irinotecan, resulted in durable responses across multiple cancer types and was well-tolerated. This included confirmed complete responses in several patients with pancreatic cancer, a notoriously difficult cancer to treat.
ATR inhibitors target cancers that lack a related kinase called ATM, which results in elevated replication stress and is an Achilles heel of these cancers. The clever part was combining the ATR inhibitors with irinotecan, which works by initiating even more DNA replication stress. In essence, these cancer cells are close to the cliff and the combination therapy completely pushes them over the edge. This is exploited in the STELLA trial, which used a two-pronged approach: patients were tested for absent or low levels of ATM in their cancers, then given a low dose of irinotecan followed by the ATR inhibitor.
The result reported for Artios’ ATR inhibitor is unprecedented for this class of drug and could be potentially transformative, especially for cancers that have high levels of replication stress and/or have lost ATM. The challenge is now raising funds for a phase three trial where the drug is tested in a much larger number of patients to gather statistical evidence that it works effectively across the population. It’s a long process already, and we’re additionally battling current market uncertainty.
Translation was viewed quite sceptically at the time the Crick first opened. Since then, attitudes have certainly changed and translation is now part of our fabric, aided by our excellent translation team, strong industry partnerships and access to funding for translation. This has helped to break down misconceptions and encourage early career scientists that other career paths beyond academia exist and are an exciting opportunity for many. Translation wasn’t in our vocabulary in the founding institutes.
The opportunity to engage in translation adds another dimension to our lab work. We’re very lucky at the Crick that we can access funds to pressure test translational ideas, try experiments and generate preliminary data, before considering applying to bigger funds like the Chris Banton Fund. Scientists starting their careers now get exposure to a different way of thinking than they would have 20 years ago. I see translation as adding another feather to our bow that will ultimately enable the Crick to improve ‘health and wealth’, one of our founding pillars!
