In this Repurposing TIN interview as part of the Early Career Innovators series, recognising the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Guillem Mòdol Caballero highlights his Repurposing TIN Pilot Data Fund awarded project, involving the use of chemokines as a novel target to improve peripheral nerve regeneration.

What is the title of your project and what does it involve?

The title of my project is “Chemokines as a novel target to improve peripheral nerve regeneration”. Treatments for nerve injuries have changed little over the last few decades and have significant limitations. The Lloyd lab, of which I am a part of, has previously identified Schwann cells, the major glial cells of the peripheral nervous system (PNS), as orchestrators of peripheral nerve regeneration. Recently, the Lloyd lab has identified a chemokine as a Schwann Cell chemotactic factor, secreted after nerve injury, that is likely to be important in directing the regeneration process. Nerve injuries are frequently associated with aberrant nerve regeneration that can lead to the formation of neuromas and neuropathic pain. Our goal is to determine whether using a chemokine receptor inhibitor, we can limit the Schwann Cell migration that leads to aberrant nerve regeneration and reduce the associated pain response.

What is the motivation behind your project/therapeutic?

The incidence of peripheral nerve injury is estimated to be between 13 and 23 per 100,000 people per year in developed countries. Currently, surgery is the conventional approach to repair nerve injuries but when there is a significant gap between nerve ends, an autologous nerve graft (autograft) is used. Although this is the current gold standard for treatment, autografts present several limitations and engineering strategies such as artificial nerve conduits have not been able to significantly improve the results. The unmet patient need include an often incomplete sensory and motor function recovery, neuroma formation or development of intractable neuropathic pain. Therefore, there is an urgent need to develop alternative approaches to treat peripheral nerve injuries and to prevent maladaptive regeneration, such as during tumour formation or neuroma development.

Can you highlight any challenges have you experienced as an early career researcher in the repurposing/translational research space?

I started working in the translational research space during my PhD and I would highlight that a particular challenge is the funding limitation. Even when the therapies results are promising and are likely to be taken to the clinic, this limitation could even slow down the research. Additionally as an early career researcher, another challenge I have faced is finding collaborations with pharmaceutical companies to help develop these therapies.

Why did you want to apply to the Repurposing TIN Pilot Data Fund?

Considering our last findings on the nerve regeneration process, we wanted to take our research towards the clinic. I thought that the Repurposing TIN Pilot Data Fund scheme would be the perfect fit to carry out this project since we wanted to use a marketed drug, and it would allow us to explore its potential as a treatment for nerve injuries associated with aberrant nerve regeneration.

How did you find the process for the TIN Pilot Data Fund? What did you learn?

The process for the TIN Pilot Data Fund was exciting and really fast. First, I attended the ACCELERATE training workshop and it helped me understanding not only what was required for the particular funding schemes but also the translational path. I also learnt how to be more concise with my scientific ideas when writing the application. My proposal was then shortlisted for a pitching event where we had to present our project. We received a brilliant training session that allowed me to learn how to address the pitch and connect with the audience. Overall, it was a great experience that will help me applying for future grant applications, especially for translational awards.

What do you hope to achieve in the 6 months duration of your project?

I hope to elucidate whether the treatment with the chemokine receptor inhibitor has an effect limiting the Schwann Cell migration that leads to aberrant nerve regeneration in our nerve injury model. The results obtained will allow us to improve the understanding of the nerve regeneration process. I hope this study will help us achieve more funding in the future to bring this potential therapy closer to the clinical translation. This could represent a major breakthrough in the peripheral nerve regeneration field due to the current treatment limitations.

About Dr Guillem Mòdol Caballero

Dr Guillem Mòdol Caballero is a neuroscientist that works as a Research Fellow in the Lloyd Lab, at the Laboratory for Molecular Cell Biology (LMCB) at UCL. During his PhD at Universitat Autònoma de Barcelona he evaluated the therapeutic benefits of delivering Neuregulin 1 (NRG1) to the central and the peripheral nervous systems, as a strategy to treat amyotrophic lateral sclerosis (ALS).

After finishing his doctoral studies Dr Mòdol Caballero joined the Lloyd Lab in 2019- experts in PNS biology. He is now focusing on understanding the complex multicellular interactions required for peripheral nerve regeneration and developing therapeutic modalities to take this research towards the clinic.

In this Repurposing TIN interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by postdoc and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Pilar Acedo highlights her Repurposing TIN Pilot Data Fund awarded project, involving the repurposing of gene P53 reactivators to treat pancreatic cancer.

What is the title of your project and what does it involve?

My project is entitled ‘Repurposing p53 reactivators for the treatment of pancreatic cancer’. TP53 is frequently mutated in pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic neoplasms, and these mutations are associated with poor outcomes, making mutant p53 (mtp53) an attractive target. Having higher levels of reactive oxygen species (ROS) compared to normal cells, cancer cells are more sensitive to further oxidative insult.

Building on this, in this TIN awarded project, I decided to take advantage of patient-derived models we had previously developed in our lab to assess the efficacy and mechanism of action of combining a P53 reactivator with Photodynamic Therapy (PDT), a light-based therapy which promotes ROS overproduction. I anticipate this strategy will exert a synergistic anti-tumour effect leading to oxidative damage and cell death of mtp53-harbouring cancer cells. The RNA-sequencing and efficacy data derived from this project will be used to apply for follow-on funding to move our research project down the translational pathway.

What is the motivation behind your project/therapeutic?

Pancreatic cancer is the 5th most deadly cancer worldwide (~432,000 deaths/year) and is projected to rank 2nd by 2030. PDAC outcomes are very poor (5-year survival rate <9%) and mtp53 expression correlate with poor prognosis. Adjuvant treatment with gemcitabine following surgery is the standard of care, however, <20% of patients are found eligible for surgery. Aggressive chemotherapy combinations, restricted to fit patients, only marginally improve outcomes so novel therapeutic strategies are urgently needed. Using a therapeutic strategy that restores the tumour suppressor functions of mtp53, and induces oxidative stress (ROS), has the potential to kill cancer cells. However, this strategy for PDAC therapy remains underexplored.

Considering the limited benefits provided by current treatment options, the variety of dysregulated signalling pathways in PDAC, and that mtp53 confers chemotherapy resistance, targeted and combination therapies hold potential to improve patient outcomes. I propose a novel approach to synergistically target the impaired antioxidative response of cancer cells, inducing extensive cell death. I expect the proposed combination to be more effective than chemotherapy alone, with significantly less systemic side effects, enabling treatment of less fit patients.

Can you highlight any challenges you have experienced as an early career researcher in the repurposing/translational research space?

As an early career researcher in the translational research field, obtaining funding to perform your own independent research is challenging and usually requires having preliminary data already available. Gaining access to patient-derived samples can also be a tricky and slow process. I could also say, surviving in academia as an early career researcher, without a permanent position is on its own, a big challenge! I have also found it challenging to develop a network of collaborators and partnerships, particularly with industry. Moreover, understating the complexity of the translational research pathway, including intellectual property (IP), and developing an entrepreneurial mind set, requires specific training.

Why did you want to apply to the Repurposing TIN Pilot Data Fund?

I had obtained some preliminary data supporting this project, but which needed further validation. The Repurposing TIN Pilot Data Fund therefore was the perfect scheme to take this work forward, while also allowing me to lead and manage a grant from scratch, fostering my career development, and supporting my career goal of becoming an independent investigator. I expect data derived from this project will attract follow-on funding to accelerate our research project into the next phase in the translational pathway.

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How did you find the process for the TIN Pilot Data Fund?

I think the guidelines were detailed and clear. The application process was well-organised, with excellent communication from the TIN Pilot Data Fund team, of which I am very grateful for the help throughout the process. I also truly appreciated the constructive feedback and advice provided by the committee.

Learn more about the support provided through the TINs

The ACCELERATE training programme has been very important in my translational progression – I think I have attended the majority of the workshops! Prior to the submission of my application, I particularly valued the seminars on IP, Entrepreneurship Skills for Researchers and ‘Grant Writing and Data Management for Translational Research’. Additionally, the pitch coaching we received was key to winning the award.

What do you hope to achieve in the 6 months duration of your project?

In this proof-of-concept study, I plan to evaluate the potential of a p53 reactivator in combination with a ROS-mediated therapy as a new therapeutic strategy for pancreatic cancer, using patient-derived models available in the lab. The resulting RNA-sequencing data will improve our understanding of the mechanisms underlying PDAC vulnerability/resistance to therapy and identify new therapeutic targets. I hope this study will constitute the foundation for subsequent grant applications to move the project closer to clinical translation.

About Dr Pilar Acedo

Dr Pilar Acedo, is a Senior Research Fellow at the UCL Institute for Liver and Digestive Health, in the Division of Medicine, based at the Royal Free Hospital campus. After receiving her PhD in Genetics and Cell Biology from the Autonomous University of Madrid (Spain), Pilar held a postdoctoral position at the Karolinska Institute (Sweden), before joining UCL in October 2015.

Her current research aims to generate patient-derived cancer models as preclinical tools to study disease progression and to predict treatment response. Pilar investigates novel combination therapies to treat pancreatic and bile duct tumours, using nanomedicine and light-based therapies. Her research interests also include the development of biomarkers and imaging tools for the early detection of pancreaticobiliary cancers, using non-invasive approaches (Follow Pilar on Twitter: @pilar_acedo).

In this Repurposing TIN interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Melissa Rayner highlights her Repurposing TIN Pilot Data Fund awarded project, establishing a relationship between a drug’s affinity for PPARγ and nerve regeneration.

What is the title of your project and what does it involve?

The title of the project is ‘Investigating the correlation between PPARγ affinity and nerve regeneration’. Previous studies I conducted demonstrated the beneficial effects of the PPARγ agonist, ibuprofen, on regeneration and functional recovery following a peripheral nerve injury. However, in vitro data has shown that PPARγ agonists with a higher affinity correlate to greater regeneration. Therefore this study will allow us to determine whether a corresponding correlation occurs in vivo. Once this is established the optimal drug could be taken forward and developed to be delivered locally to an injured nerve through a biomaterial or injection.

What is the motivation behind your project/therapeutic?

Peripheral nerve injuries have a high prevalence and can be debilitating, resulting in life‐long loss or disturbance in function, which compromises quality of life for patients. Current therapies use microsurgical approaches to repair the nerve but there is the potential for enhancing recovery through other therapies. Following an injury, a repaired nerve can regenerate and grow back to the target organ (e.g. muscle or skin) to restore function, however, outcomes are generally poor with incomplete restoration of function. This is due to regeneration being remarkably slow, ~1mm/day. The problem is that there are no current treatments available to increase this regeneration rate. The research we have done has identified drugs and a local delivery platform that could provide a therapy for this clear clinical need.

Why did you want to apply to the Repurposing TIN Pilot Data Fund?

Following an initial experiment that I conducted during my PhD I had found an interesting correlation between a drug’s affinity for PPARγ and its capacity to increase nerve regeneration. I wanted to confirm whether this correlation is reproduced in vivo but unfortunately I had no funding to conduct the study. I applied for the TIN pilot fund so I was able to take this work forward and move it closer to the clinic. In addition, the TIN pilot fund gave me an opportunity to apply for a grant as the lead applicant which is a stepping stone in my development towards my goal of building an independent research career.

The UCL TINs are hoping to run another round of Pilot Data Funds in the summer. Subscribe to the TINs newsletter to keep updated.

How did you find the process for the TIN Pilot Data Fund? What did you learn?

The application process gave me the opportunity to write my first grant application as a lead applicant. Furthermore, the application process involved a Dragon’s Den event where we had to pitch our project/therapeutic. This was a new experience and allowed me to develop a lot of new skills. I had the great opportunity to attend an ACCELERATE pitching coaching session and receive one-to-one feedback on my presentation style.

What do you hope to achieve in the 6 months duration of your project?

I hope to be able to establish a relationship between a drug’s affinity for PPARγ and nerve regeneration in vivo which will enable us to identify a leading repurposed drug for use in peripheral nerve injury. I can then further develop local controlled drug treatments with a more potent PPARγ agonist which may be more commercially competitive than ibuprofen. I hope this will provide positive data which can be used in subsequent bids for funding which will allow me to move this work closer to translation into the clinic.

About Dr Melissa Rayner

Dr Melissa Rayner qualified as a pharmacist in 2014 before starting a PhD at the Centre for Doctoral training in Advanced Therapeutics and Nanomedicines at UCL School of Pharmacy. Her PhD was a multi-disciplinary project combining tissue engineering and drug development to improve regeneration and functional recovery following peripheral nerve damage. During this time she also worked for the UCL spin-out company, Glialign, to develop a stem cell based tissue engineered product to repair peripheral nerves.

Melissa is currently a postdoctoral research fellow working in the UCL Institute of Prion Disease on a project funded by the Department of Health. The project involves developing a cell based assay that could be translated to the clinic as a tool to diagnose Creutzfeldt-Jakob disease. Through collaborations with UCL School of Pharmacy she still continues her research on regenerative medicine for peripheral nerve injury, including work on the development of local drug therapies to improve regeneration.

In this Repurposing TIN interview as part of the Early Career Innovators series, acknowledging the amazing translational work being done by early career and non-tenured researchers within the UCL Therapeutic Innovation Networks (TINs), Dr Jennifer Rohn highlights her Repurposing TIN Pilot Data Fund awarded project, involving the reformulation of the common chemo drug mitomycin-C for bladder cancer.

What is the title of your project and what does it involve?

My project is entitled “Repurposing mitomycin-C to expand opportunities for bladder cancer sufferers”. We decided to take advantage of a previous therapy platform we developed for urinary tract infection (UTI) to see if we could retrofit it for bladder cancer therapy with a few tweaks.

A novel micro-encapsulation process offers robust tissue penetration of generic drugs

Our UTI solution, which is currently being commercialised by the UCL spinoff AtoCap in collaboration with engineering colleagues at UCL and Oxford, is a reformulation of the common antibiotic nitrofurantoin. The antibiotic is mixed with the FDA-approved polymer PLGA using patented technology, resulting in novel microcapsules that are designed to be delivered directly into the bladder via catheter, and once there, to penetrate robustly, delivering drug deep into the bladder wall where it’s needed. In this TIN award project, we are going to reformulate the common chemo drug mitomycin-C using the same platform, in the hopes that the resulting microcapsules will allow deep bladder delivery of this important drug which is currently of limited use because it’s difficult to get it into the tissues.

In parallel, in order to test and troubleshoot our prototype chemo-capsules, we are adjusting a human bladder “organoid” model developed in my lab so that it is equipped with fluorescent cancer cells. Using this modified platform as a test-bed, we should be able to do some great experiments with the prototype capsules to see if they can penetrate and kill cancer cells better than free chemo drug. This data package will be used to attract follow-on funding to help speed our solution down the translational and commercial pathway.

What is the motivation behind your project/therapeutic?

Bladder cancer is a bit of a neglected disease; it’s the most expensive cancer of all to treat, but unlike other cancers, outcomes have not improved for decades because there hasn’t been much research into mechanisms and new drug discovery. We are focusing here on non-muscle-invasive bladder cancer (NMIBC). Of 300,000 new NMIBC cases per year worldwide, low/intermediate-risk patients (~80%) would benefit from more penetrative chemotherapy, and it might newly enable treatment of high-risk forms and relapsed patients. The current standard of care is surgery, followed by traditional chemotherapy and Bacillus Calmette–Guérin (BCG). Recent advances in immunotherapy, while promising, are suitable for only a limited number of advanced cases, and are associated with severe side effects. Patient support groups repeatedly identify improved NMIBC treatments as the top priority.

Can you highlight any challenges have you experienced as an early career researcher in the repurposing/translational research space?

Although I’ve been a scientist for a long time, I only recently started up a lab of my own due to my convoluted career pathway in and out of academia. Just staying afloat in academia as “a mature ECR” is a challenge in itself, and though I still don’t have a permanent position, I am clinging on in there. I think reformulation is particularly tricky. Although the route-change offers a streamlined regulatory pathway, which lowers costs, it is sometimes difficult to persuade investors that a generic drug can be reinvented into something new and profitable, and your patent position has to be really solid. It’s been interesting to be involved in a university spin-off – I was recently made Chief Scientific Officer, so I get exposed to a lot of the business side as well as the science. It’s a truly fascinating world and I am still learning all the lingo!

Why did you want to apply to the Repurposing TIN Pilot Data Fund?

I’ve been involved in the TIN for a while and it seemed a natural fit for my project. We need pilot data to get further funding, but you can’t do research without money. The TINs Pilot Data Fund therefore was a really attractive way to get around that “chicken and egg” problem.

Learn more about the TINs

How did you find the process for the TIN Pilot Data Fund? What did you learn?

I think the whole thing was beautifully organised and I particularly valued the professional pitch training we received. It not only helped me win the award, but I can use these skills to help improve my pitching to various investors. The organisers were also so helpful throughout the process.

Translational training from UCL ACCELERATE

What do you hope to achieve in the duration of your project?

Things have been very challenging because of COVID and even though the labs are now open, everything is going a lot more slowly due to ongoing lab occupancy restrictions. Thankfully the scheme has been extended for those experiencing issues due to restrictions of the pandemic, to give us all a little more breathing space. Things are going very well so far – we are nearly ready to merge our fluorescent cancer cells with our healthy bladder “organoid” and we expect to have our data package completed right on schedule.

About Dr Jennifer Rohn

Dr Jennifer Rohn, a cell biologist, is Principal Research Associate and Head of the Centre for Urological Biology in the Department of Renal Medicine in the Division of Medicine, based at the Royal Free Hospital campus.

After receiving her PhD from the University of Washington in Seattle studying virus evolution, she held several post-doctoral positions in academia and industry in the Netherlands and in the UK (along with a research career break in science publishing) before settling into her current role. She and her research team are interested in understanding urinary tract infection and as part of this, they seek to find novel therapeutic delivery mechanisms that facilitate penetration of the bladder wall to kill bacteria sheltering within. More recently the lab has branched out into bladder cancer, another disease in need of better penetrative solutions for chemotherapy. Jennifer is also a prolific writer and science communicator in her spare time, and she has published three novels about scientists (a genre known as “lab lit”).