As Professor Bob Brown prepares to retire we caught up with him as he reflected on his career and his involvement in the ECMC network.
Can you tell us a little about your background and why you got into cancer research?
My first degree was in Biological Sciences at Edinburgh University, with a particular interest in genetics and developmental epigenetics. I did my PhD on ionising radiation induced mutagenesis at the MRC Radiobiology Unit in Harwell, followed by a postdoc on identifying oncogenes at the German Cancer Research Centre in Heidelberg, before picking up my interests in epigenetics again at the Beatson Labs in Glasgow.
I have always been interested in understanding the mechanisms and drivers causing diseases such as cancer. I became motivated about translational cancer research after working with Prof Stan Kaye, at that time Head of Medical Oncology at Glasgow University. Working with Stan and the Glasgow trials team got me excited about how understanding mechanisms can lead to improved ways of treating patients through evidence based, clinical trials.
What has been the highlight / most rewarding part of your career?
Different things at different times have been important to me. In the last couple of years teaching and education have been very rewarding. However, at the beginning of my career it was all about getting results (and of course publications!). Together with Prof Ged Brady, we were one of the first to clone a murine oncogene and identify the oncogenic mutation. At that time it took three years of hard work, now we could probably do it in a day.
Getting the experimental result that supports your hypotheses is rewarding, although sometimes it’s the result you don’t expect that is the most exciting. At the Beatson we were hunting recessively acting drug resistance genes, which serendipitously led to identifying epigenetic regulation of DNA mismatch repair genes in platinum resistant ovarian cancer. I have subsequently spent the last 25 years working on epigenetics as a driver of drug resistance in cancer.
In retrospect, the most rewarding part of my career has been helping develop laboratory-based concepts into clinical trials and watching a multidisciplinary team combining to rationally plan and deliver the trial.
What impact has the ECMC network made over the past almost 15 years?
I think I was one of the first non-clinician, non-pharmacologist to join the CRC Phase I/II committee, which was a precursor to the ECMC network. This was a forum for discussing the design of high quality, academic-led, early clinical trials with robust biological end-points (and identify why poorly designed trials were missed opportunities to inform patient-centric cancer research). It has been a pleasure to watch how the ECMC network has helped deliver trials, educate investigators and benefit patients following on from those original machinations.
If I had to identify only three key impacts that the ECMC network has had, then these would be:
1. Education: Helping investigators understand the importance of drug:target (and non-target!) interactions in patient tissue and how early trials can inform future patient selection. The Junior Investigator Network Group has been particularly important in this impact.
2. Quality assurance of data: providing a framework for how high quality clinical and biological trial endpoints inform drug development and patient treatment in a robust and ethical manner with appropriate governance.
3. Creating a collaborative national network for sharing expertise and successfully delivering better treatments to patients.
Within cancer research what is the biggest change you have seen over your career?
Our understanding of the complexity of the disease. This is partly driven by genomic and other technologies now available, but also by the types of questions we are able to address in the lab. For instance, we have moved from relatively simple established tumour cell line models to analysis of patient-derived tissues that better reflect the heterogeneity of the disease. Established cell lines in their time have been fantastically useful as reductionist laboratory models that have provided great insight into individual mechanisms and signalling pathways, leading to discovery of important novel treatments. However, they over-simplify and fail to capture key aspects of tumour development, such as the tumour microenvironment, immune responses and tumour adaptation.
What would you say are the biggest opportunities and challenges in experimental cancer medicine?
The greatest opportunity is integrating the knowledge and wealth of existing data into actionable targets that allow the development of better cancer therapies for all patients. Integration of knowledge is not just about Big Data and Big Science: small can be more agile and innovative. Convergent approaches that address key research questions and clinical unmet needs can build holistic understanding that deliver better treatments to patients. This will require involvement of the research community across all UK clinical and academic institutes and not just in a small number of specialised centres.
There are lots of big challenges in cancer research, but difficult to know where the next big breakthrough will come from and even trickier to immediately recognise it when it does. Twenty years ago cancer immunology was considered a niche area by the research community, but now is one of the most exciting areas for new therapy development. Genomics has answered many important questions about cancer risk and tumour initiation. But, genomics is only part of the story for how a tumour will adapt to treatment and epigenomics may be much more informative (as many of my colleagues will know; I was bound to say that!). Until we successfully tackle the problem of drug resistance (or prevent the acquisition of drug resistance), we will not substantially improve current survival rates for the majority of cancer patients.
What would you like to see experimental cancer medicine look like in 10 years from now?
I would like us to have changed the paradigm of how we do cancer clinical trials for experimental cancer medicines. We have still to fully incorporate biological endpoints and patient stratification into adaptive trial designs. We are still using trial designs developed for cytotoxics, which are less appropriate when clinically evaluating molecularly and immunological targeted agents. While the success of the COVID vaccine trials has been partly about funding, it’s also been about political will of the research community to adapt trial design to the clinical need.
Ways of monitoring a patient’s tumour through their treatment and as the tumour recurs and evolves will be crucial. There always will be a place for large, randomised controlled trials, but experimental medicine approaches that monitor and can adapt in a personalised and preventative manner to give the right choice of treatment at the right time will have major impact on patient survival. A major challenge is in identifying rational approaches to the optimum schedule and combination of existing drugs that simply have not been used in the right way yet to treat cancer.
What are you most looking forward to about your retirement?
Spending time with my wife and family, dusting off my hiking boots, tuning up our 1975 VW Campervan, finding the golf clubs, learning how to repair and make beautiful stained glass. Also staying a little involved in education and research – we have a novel epigenetic compound we have developed at Imperial College that it would be great to take forward as an experimental cancer medicine!