Q: What was your journey to the position that you hold now? 

A: I trained in medicine originally, and as part of that I did an intercalated BSc in Pharmacology, already then I knew that I was more interested in the academic side of medicine. I did about 10 years training in oncology, as part of that I did a 4-year PhD focused on the role of TNF-α in ovarian cancer, as part of that I discovered upregulation of a gene that makes Arginine, ASS1. Leading to the current research that I do focusing on arginine dependency in cancer. I was then awarded a fellowship which at that point I was a consultant medical oncologist, allowing me to pursue my interest in science alongside my clinical interest, focused on patients with lung cancers and melanoma, then I was successful in obtaining a professorship. So, I am currently a Professor in Medical Oncology at Queen Mary University of London with a Consultant position at Barts. 

Q: Did you know that you wanted to pursue academics or were you set on the medical route? 

A: When I was doing my A-levels I was already interested in academics and wanted to do a  PhD, so I applied for Medicine. I realised that was something I would want to do later on and I was already interested in oncology, so I guess all of those fitted in but I wasn’t aiming for professorship, that just sort of happened along the road as it were. 

Q: Recently you published your group’s research in JAMA Oncology on a novel Clinical Trial targeting Mesothelioma, could you tell us a bit about how this trial was set up and your main research findings? 

A: The Phase 3 trial is the first ever to test arginine deprivation, with a drug called Pegargiminase made by Polaris Pharmaceuticals in combination with chemotherapy. ASS1 came up during my PhD in a DNA profiling experiment. I didn’t have many hits, but one of them was ASS1. Polaris developed a drug that showed tumour reduction in mice by starving them of arginine, stimulating my interest in seeing, could I do this in ovarian cancer? Ovarian cancer has high levels of ASS1, so despite the fact I was trying to starve them, I couldn’t kill the cells. I came across a colleague, Dean Fennel, now a Professor in Leicester, who gave me some mesothelioma cell lines. I tested those and I could kill half of them, as they had very low ASS1 expression. We obtained a grant from MRC CRUK for a small UK trial with about 70 mesothelioma patients, finding that by removing arginine, we could slow down the mesothelioma growth. We didn’t see a difference in survival, but we saw tumour reduction, from this we combined that with chemotherapy. By starving mesothelioma cells that had lost ASS1, we could improve their sensitivity to the standard anti-folate drug Pemitrexed. Back in the clinic, we treated around 100 patients across different tumour types, focusing on mesothelioma. We got responses by combining Pemitrexed with platinum and Pegarginimase. This was a positive global Phase 3 trial; in oncology this is quite a rare event, only about 10% of Phase 3 oncology trials are positive. This opened up an interesting area in cancer metabolism and rejuvenated the struggling field. It’s very hard to do because a lot of these enzymes are important in our normal cells, so how do you find that therapeutic window where you can specifically attack cancer cells. The beauty about arginine, is that our cells don’t actually require it as an essential amino acid. Cancer cells switch off ASS1, giving them an Achilles heel, where you can starve and exploit them, and that’s what we’ve shown in this combination study. 

Q: What do you believe makes this therapeutic approach unique, and are there any further applications that you see from it? 

A: This is not the first time amino acid deprivation has been done, in the 50s an approach was discovered in acute lymphoblastic leukemia (ALL). The standard drug (asparaginase) is now used in the multimodality treatment of childhood ALL. Yes, arginine is unique in its own field, but it’s been developed from that very successful study, but unlike asparaginase, I think that arginine starvation potentially has much more applicability. Beyond leukemia and rare lymphoma, it’s not found in widespread use, partly because its quite toxic. But with our approach, looking at different cancers, there’s always patients that may benefit from arginine starvation. A global phase 3 is currently underway in sarcoma with pegargiminase. There is also a study currently underway in the US, using pegargiminase with radiotherapy and another chemotherapy drug. Looking forward, I think there might be a number of other cancers where we might be able to improve the treatment simply by removing arginine from the cancer.  

Q: What impact do you think this will have for patients suffering with mesothelioma currently? 

A: The therapy is under review by the FDA, and if approved we hope next year it will become available on the market and be accessible for patients. It needs to go through regulatory bodies, the EMA, the UK regulator the MHRA, and other countries will be looking at it. Mesothelioma is a global disease, but in the UK now, we have the highest death rate in the world. With around 2,500 deaths, 2,700 diagnoses, its expected to increase especially in developing countries where asbestos is unfortunately being used in construction, especially China which uses the most asbestos construction. 

Q: You’ve been working on cancer research for 2 decades since your PhD, how does it feel that all of your hard work has had such an impact and what does this breakthrough mean to you? 

First, I think it is very important for patients, a novel treatment, as an oncologist that’s the ultimate dream that you want to develop something. I’ve been fortunate that I’ve been driving that from the bench to the bedside over several iterative cycles and that’s quite a rare event as I’ve been told. It’s also an extremely satisfying endeavour that I’ve been involved with and the fact that I have several patients alive today because of this treatment makes it even more relevant, to be involved in a project that delivers improved care for patients is satisfying for both doctors and researchers. 

Q: If you could go back to your undergraduate self, what advice would you give him, do you have any final ‘words of wisdom’ ? 

A: I think the most important thing I would say reflected in my career, is never give up if you believe in something that you can achieve. I’ve had people along my career who were negative to me, saying “this isn’t going to work”. But I’ve had other people who were very supportive, so I think even when others say it’s something not worth pursuing, you need persistence and perseverance. 95% of the time research is pretty gloomy and has a lot of negative results. But you shouldn’t let that colour your outlook. Studying in depth is very important in science, you really have to go deep and put things into context. Not everything that is in the literature is correct, unfortunately, there’s fraudulent publications which has affected science. I think you have to be very careful, scrutinise the data, and generate hypotheses that you can test. Another thing is don’t be shy of collaborating, I think it’s very important and science is a team effort, but at the end of the day you have to drive it if you really want to achieve something, you have to go for it, and don’t give up. 

Image: Barts Cancer Institute