IMI: Why was MARCAR needed in the first place?
Jonathan Moggs: When it comes to developing innovative medicines, one of the challenges for the pharmaceutical industry includes the safety assessment to make sure that the medicine is as safe as possible for humans. One of the big questions we ask during the mid-to-late phase of drug development is: does the drug have any potential to cause cancer? This is, of course, a major concern and there are regulatory guidelines that help the pharmaceutical industry apply that question in a very rigorous way. We call that cancer risk assessment. The challenge in the field is that many of the animal studies or pre-clinical studies that are performed are imperfect in terms of predicting the risk for humans. The holy grail of the field would be to measure something very early, in a few weeks of dosing a laboratory animal with the candidate drug, to predict whether or not any tumours will develop. We’re not there yet, but we believe a lot of the MARCAR know-how, data, tools and models can take us in the right direction.
IMI: Which project accomplishment are you most proud of?
Jonathan Moggs: We started with the hypothesis that epigenetic changes are fundamentally important for drug-induced carcinogenesis [The epigenome comprises all of the molecular changes to chromatin (a complex of DNA and proteins that forms chromosomes within the nucleus of cells) that regulate the activity (expression) of the genes within the genome]. The early effort at MARCAR, and that’s one of our first achievements, was to optimise innovative epigenomic profiling technologies in complex tissue samples. This enabled us to publish some important stories around a relationship between drug exposure, tumour formation and a measurable change in the epigenome in the liver tissue of animals. Having established those methodologies, we then began asking the question – what is changing in the epigenome upon drug exposure, and why might that be an important functional consequence, ultimately leading to cancer?
When we looked at our complex epigenomic datasets we were very excited during those early years in MARCAR to find some very important regions of the genome which were switched on or off during exposure to drugs which are known to cause cancer in rodents. These changes occurred in concert with physiological changes in liver tissue. The epigenetic switches affected genes that had been very recently described in the academic field as key in returning a cell to a pluripotent, stem-cell like state. Why is that important? Well, stem cells can become many different types of cells, that is their property by definition. We speculated and hypothesised that re-programming of adult cells by carcinogenic compounds to a more stem-cell like state may be an important early step which later contributes to tumour formation.
This pluripotency hypothesis is not fully proven but it is very interesting. That is a fantastic story and was really one of many high-points of the project. It’s one of the first times we’d found new data, and we realised the power of how quickly we could advance that observation because we were a consortium. Otherwise, it would have been a multi-year follow up – which would have slowed progress and lessened the impact of these important observations.
IMI: The new imaging method MARCAR developed will contribute to the reduction in number of animals used in preclinical studies. Could you tell us a bit about that?
Jonathan Moggs: When you’re tracking cancer formation in animals, it takes a long time to get tumours formed by drug exposure. Every time you want to see if something has changed, you have to look at the tissue, which means sacrificing the animal. In MARCAR, we used an MRI [magnetic resonance imaging] scanner for mice, a little one. They are gently anaesthetised, then you scan them, and with some clever trickery developed by the MARCAR partners, you can see early tumour masses in the liver at only 1 mm in size. In order to follow tumour growth, you can just rescan the same animals over time without interfering with them. This method dramatically improves the efficiency of preclinical safety studies because you can scan the same animals to determine the optimal time to make a more detailed assessment of the tissue. This means you need fewer animals, and the quality of the knowledge obtained from the study dramatically increases.
IMI: How did the project change the field itself? What were its main contributions?
Jonathan Moggs: It’s fair to say MARCAR and its output are leading the characterisation of drug-induced epigenetic changes associated with carcinogenesis. There are other academic teams doing some similar studies but we by far made the most advances in that question globally in recent years.
IMI: Would it have been possible to do all this without IMI?
Jonathan Moggs: It would have been possible to run the in-vivo studies that we performed and to profile them with standard gene expression tools, as long as someone had the funding. But it wouldn’t have been possible to make the interpretation and do the follow-up on the hypothesis because that depended upon multiple partners. Nor would have there been the possibility of really strongly enhancing the ability to look at the epigenome in tissue. I don’t think we would have the scope as individual partners to go deeper into the context of the drug-induced changes.
IMI: Has the industry changed the way they’re doing things as a result of this project?
Jonathan Moggs: It’s too early to say on an industry-wide level, but I am aware of several industry stakeholders who have learned a huge amount from being connected to the MARCAR experience, and certainly have taken the opportunity to think about how that learning from the MARCAR project can enhance the way they assess cancer risk during drug development.
IMI: What will be the long-term impact on the industry and the drug development process?
Jonathan Moggs: We hope that as these approaches are further refined and adopted by multiple sectors both in academia and the industry, the understanding of the mechanisms of tumours caused by drugs in animals will be more rigorous, science-based, and will enable us to make better decisions about the human relevance.
IMI: How will the patients benefit from this project in the long-term?
Jonathan Moggs: Cancer risk assessment needs to be applied to all innovative medicines. MARCAR contributed to the scientific rigour and strength of the cancer risk assessment, by which we will ensure that safer medicines reach patients, and in some cases accelerate the time it takes for those medicines to reach patients. What causes delays is having an unexpected tumour finding in pre-clinical animal studies that we cannot easily explain; this prevents us from having a good way of making an accurate cancer risk assessment for humans. MARCAR’s science, technology and models should enable those kinds of question to be answered more quickly and more comprehensively.
IMI: What was the most rewarding aspect of the project for you personally?
Jonathan Moggs: Of course, there was the initial challenge of getting everything correct and running with the new IMI call. However, the experience of coming together roughly every 6 months as a full team of 30-40 people, and having complete freedom to share primary data and findings, with no delay, because we were all under the umbrella of the project agreement, and the reactiveness and response of partners to those suggested ideas, that was excellent. It was a really fantastic experience because we had just about long enough – if it was one or two years it probably would have been disappointing. But having 5 years enabled us to make some real, impactful discoveries and to follow up on them within the same team. And that was important. It was a pleasure to be part of that public-private partnership because science was the common currency among different stakeholders in the consortium (regulatory, academic, or industry).
IMI: Now that the project has ended, what happens next?
Jonathan Moggs: Currently, MARCAR is actively discussing the best way to gain further value from its assets, such as the database and biobank with tissue samples from in vivo animal studies. We have several options, one of which is that MARCAR partners fund activities to pursue further assessment of those samples. It is also very important to share the outcome of our studies with the global community. Some of the more important meetings in the near future include the Health and Environmental Sciences Institute workshop in spring 2017. This workshop will bring together industry, regulatory and academic scientists to debate the importance of advances in cancer risk assessment based on genomic technologies. The epigenetic work that MARCAR has done will be essential to that debate.