2021 journal ECR prize-winners interview

Each year the British Journal of Pharmacology (BJP) and the British Journal of Clinical Pharmacology (BJCP) award prizes for the best papers published by early career researchers over the previous year. Corresponding authors can nominate their eligible co-authors upon submission, and the senior editors judge the nominations. Awardees receive a cash prize, a certificate and one year of complimentary membership to the British Pharmacological Society.

In 2021, the winner for BJP was Liliana Raimundo of the University of Porto, Portugal, for BBIT20 inhibits homologous DNA repair with disruption of the BRCA1–BARD1 interaction in breast and ovarian cancer. For BJCP, the winners were Thomas Buters of the Centre for Human Drug Research and Leiden University Medical Centre, Netherlands, for Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers, and Franca Morselli of King's College London for Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure-independent mechanisms in patients with or at risk of type 2 diabetes mellitus.

We interviewed our winners to find out more about their work, careers and interests.
 

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What are the key points of your article and their implications?
 
Franca: My group and I demonstrated that a 6-month trial of dietary nitrate in the form of beetroot juice decelerated the thickening of the intima-media in the carotid artery (CIMT), in a population at high cardiovascular risk with diabetes and hypertension. CIMT is an early marker of atherosclerosis; thus, dietary nitrate may reduce the progression of atherosclerosis in these patients. Beetroot juice is relatively cheap and widely available and could represent a cost-effective addition to more traditional cardiovascular prevention strategies, or an alternative for patients with multiple medication intolerance.

Thomas: Unlike intravenous lipopolysaccharide (LPS) administration, which is a widely used method to study systemic inflammation in humans, intradermal LPS administration had only been done once in the past. Our goal was to thoroughly characterize the response to intradermal LPS and by doing so we created a local inflammatory challenge model. The intradermal LPS challenge has several advantages over the intravenous LPS challenge, for instance it is a lot less burdensome for the volunteers: there are no systemic side effects like headache or fever. Another great advantage is that it not only allows us to study anti-inflammatory properties of systemic drugs, but that it can also be used to study topical anti-inflammatory drugs.

Liliana: Advances in the treatment of triple-negative breast and ovarian cancer remain challenging. In particular, resistance to the available therapy, by restoring or overexpressing the DNA repair machinery, has often been reported. Herein, this article disclosed BBIT20 as an inhibitor of homologous DNA repair by disruption of the BRCA1-BARD1 interaction. This triggers a nuclear-to-cytoplasmic BRCA1 translocation, cell cycle arrest and downregulation of homologous DNA repair-related genes and proteins, with subsequent enhancement of DNA damage, reactive oxygen species generation and apoptosis, in triple-negative breast and ovarian cancer cells. BBIT20 also displayed pronounced antitumour activity in patient-derived cells and xenograft mouse models of ovarian cancer, with low toxicity in non-malignant cells and undetectable side effects in mice. Additionally, it did not induce resistance in triple-negative breast and ovarian cancer and displayed marked synergistic effects with cisplatin and olaparib. These findings allowed us to add an inhibitor of the BRCA1-BARD1 interaction to the list of DNA-damaging agents. Importantly, either as a single agent or in combination therapy, BBIT20 reveals great potential in the personalized treatment of aggressive and resistant cancers, particularly triple-negative breast and advanced ovarian cancer.

What excites you about pharmacology?

Franca: Pharmacology brings innovation into clinical practice, and this is the aspect I find the most thrilling. From the identification of a pathophysiological pathway, through the choice of a potential target, to the test of the molecule that could influence the course of the disease: clinical pharmacology empowers me to interfere with the course of the disease, to make a difference in my patient’s health. 

Thomas: The multidimensional aspects within drug development in particular excite me the most: it all starts with a disease and the mechanism behind it, then there are unmet medical needs, and finally the development of a new drug that should fulfil those needs. In the end it should be the patient that is benefitting from all our research.

Liliana: One of the most fascinating aspects of pharmacology is the daily opportunity of bringing new ideas and treatment possibilities to so many diseases. There’s still so much to explore to help patients and improve life quality, that this field of study will never lose its relevance. Also, pharmacology can be studied with different purposes, as we can either focus on pathways and mechanisms of disease to identify new drug targets or find promising drug candidates. This makes it necessary for the researcher to acquire knowledge in multiple fields that allow them to pave the way to new discoveries.

What are you currently working on? Take us through a typical day in your life.

Franca: I am a cardiology trainee in the Kent, Surrey and Sussex region, and I am currently spending my first year of training at the Queen Elizabeth the Queen Mother Hospital in Margate, Kent. The life as a cardiology trainee is very busy, and most of my time is spent between on-calls and learning core cardiology skills, like echocardiogram, angiography, and pacing. Academic skills are also essential in the field of cardiology, and although it can be a challenge to find the time and energy, I haven’t stopped working on some research projects. At the moment, I am working on a systematic review and meta-analysis of randomised clinical trials evaluating pharmacological treatment of aortic valve disease.  

Thomas: When writing our paper, we came up with more exciting questions. Two of those are: 1) can we prove that the IL-1β response that we observed after intradermal LPS administration is indeed mediated by the NLRP3 inflammasome? 2) does intradermal LPS administration trigger the formation of Neutrophil Extracellular Traps (NETs). To answer those questions, we performed a follow up study. Currently, we are in the middle of analysing the data, and so far, it looks promising!

Liliana: When I finished my PhD, I had to make the difficult choice of changing career path. It is not easy for researchers to always depend on scholarships and funding to support our research. Also, I finished my PhD during the pandemic, which just made things a little more complicated for researchers who wanted to continue other studies besides COVID-19. During this time, I applied for both research and lab diagnostic technician positions. Now I’m working at UNILABS Portugal, in the Molecular Biology department. At first the focus of my position was only on COVID-19 detection and now it is dedicated to the diagnosis of different microorganisms and genetic mutations in patients' samples. One of the most interesting aspects of being part of this team is the constant will to find new ways to improve patients' care through the improvement and implementation of diagnostic methodologies and the opportunity to be involved in new studies. Therefore, I go to work in the morning to spend the day in the lab with my teammates. My work includes organizing the day's work, carrying out experiments and data analysis.

What are the biggest challenges you have faced?
 
Franca: When I moved to the UK from Italy, the first job I got was as Clinical Research Fellow. I did not have much research experience, and that was exactly why I applied for the job. My background was almost exclusively clinical, and I was looking forward to gaining new skills, and being part of something I had only read about in scientific papers. I was so excited about going from applying the science to making the science. At the beginning, this proved not easy at all, and I felt very discouraged at times. Not only was this a new area for me, I was in a new country, with a different healthcare system, policies, and culture. Determination, flexibility, and the amazing support of my co-workers and mentors, were key in the whole process, from learning the basics to producing research.  

Thomas: In clinical research one should not expect to get  results overnight. It really is a process of months or even years of team effort before you start to acquire results. So, staying motivated during day-to-day tasks was probably the biggest challenge. But in the end, when you finally get great results that lead to publication, it really pays off.

Liliana: Since the beginning this project was not an easy task due to its novelty. Actually, there’s still a lot to explore about BBIT20, its applicability and BRCA-BARD1 interaction. Also, although the main research focus of Lucilia’s Saraiva research group has always been the identification of pharmacological modulators of human cancer-related proteins, mostly of p53 family, with BRCA proteins we were entering a completely new world. Therefore, due to the novelty of the project, we had to acquire a strong set of data to prove our hypothesis and be able to get some financial support. Despite the difficulties, we were able to assemble a brilliant group of researchers from different institutions that also believed in the project and allowed me to work and learn from them. This was one of the most wonderful parts of the work.

What do you enjoy doing outside of work?

Franca: I like sport and exercise, especially outdoors activities, such as running and cycling. I am a huge fan of CrossFit, a discipline which integrates aerobics and weightlifting, and I also took part in CrossFit team competitions. I very much enjoy long walks in the park with my Jack Russel – she is high intensity training too! I enjoy live exhibitions, especially musicals, and thankfully my to-see list of West End shows is still long  

Thomas: I enjoy cooking and organizing dinners for friends and family. Cooking is something I already enjoyed before the COVID pandemic struck, but the pandemic really gave my girlfriend and me the incentive to bring it to the next level due the fact that restaurants were closed most of the time. Our goals were to offer guests a restaurant experience at home and so far, I think we succeeded.

Liliana: In my spare time, I like watching TV shows, listening to music and reading. I love to go on trails, we have really amazing ones in Portugal, and spend time with my friends and family.

What’s next for you, and what do you hope to achieve over the course of your career?

Franca: Cardiology training is a long journey, full of challenges but also full of opportunities. In about two-years I will have finished my core cardiology training, and I would like then to take some time out of training and undertake a PhD in my chosen area of subspecialty. I hope I will be able to pursue a career as a clinical academic cardiologist.  

Thomas: Although I’m still writing my PhD thesis, I am now working as a physician at the internal medicine department to gain broader clinical experience. After that I want to apply for a dermatology residency program. The ultimate career goal would be to work as a dermatologist preferably at a university medical centre where I can combine patient care with research.

Liliana: I am currently expecting my first child, so my immediate plans are focused on maternity and all that comes along! Long term, I hope to re-establish myself as a researcher and be involved in drug research and development in some way. Indeed, one field that I would love to explore are clinical trials, being on the next step of drug development. Otherwise, I would also love to develop some projects of basic biology, trying to understand the mechanisms of resistance to some drugs and the association to prognosis.

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