Radiotherapy activated materials for enhanced cancer treatments

Lead Research Organisation: University of Nottingham
Department Name: Sch of Pharmacy

Abstract

Cancer remains one of the most significant causes of mortality worldwide, with 8.2 million deaths and 14.1 million new cases reported in 2012 alone (World Health Organization, 2012: http://www.who.int/mediacentre/factsheets/fs297/en/), and a cost to the EU of 126 billion Euros in 2009. Chemotherapy is currently a major approach for treating cancer but a continuing concern is the inability to deliver therapeutic doses of drug directly to cancer cells without affecting normal cells. A new generation of medicines is needed to address the current shortcomings and to target complexities associated with differing cancer types, disease progression and tumour anatomies. The focus of this project is triple negative breast cancer (TNBC) which affects 12% of the 1.4 million newly-diagnosed breast cancer cases each year. There are very limited treatment options for TNBC because this form of cancer does not express any of the three biomarkers that are targeted by current therapies (including drugs such as Herceptin). For this Fellowship project we target TNBC with new chemotherapeutics which have been specifically designed to operate alongside radiotherapy, to exploit some changes in biology which occur during and after radiation damage. It is estimated that ~ 60% of cancer patients will receive radiotherapy, yet to date, chemotherapeutics have rarely been designed to recognise this clinical fact. The project will therefore explore a new and powerful means to combine radiation and chemistry to target cells which would otherwise evade therapy.

Planned Impact

Impact from the Fellowship will arise through new materials for an important unmet medical need, but also through a change in 'research culture' for the Fellowship team. We are building on some established chemistries but with some new components specifically targeted to the therapeutic regimens currently in use in the clinic. One of the main drivers for impact will be the embedding of the Fellowship within the industrial pharmaceutical development pathway, such that lab formulations designed to exploit biological mechanisms observed in the clinic are rapidly taken to go/no go decisions in the industry context. Health economics and regulatory decisions are included in the efficacy review of the new materials from the start - a significant departure from normal academic lab end-points.

Outreach and Advocacy will involve the full Fellowship team. We have experience of science outreach (YouTube, Royal College of Art, Science Festivals) and will work with oncology experts including John Saunders and Breast Cancer Now to establish appropriate outreach mechanisms for the sensitive subject of cancer.

The medical needs for breast cancer are all too apparent, with > 1.4 million new cases per year, and ~ 200,000 in the Triple negative classes. In addition to the mortality and morbidity, the affects on patients' families, there are economic losses of ~£1.5 bn due to breast cancer in the UK alone. This project is aimed to have technologies fast-tracked to new medicines via the combination of radiobiology-inspired therapies and innovative chemistry formulations.
The project may in the long term also impact on other cancers such as non-small-cell lung cancers. The difficulties of delivering drugs to these cancers by inhalation have meant that many injectable formulations for treating lung cancers are being developed. These include Abraxane and BIND-014 (both in Phase II trials). However, neither Abraxane or BIND-014 have drug release mechanisms which take account of the changed biology of radiation treated cells. As with TNBC, there is a compelling case for new formulations of drugs which could be activated in radiation-treated cells.

Impact also lies in encouraging and retaining key skills and investment opportunities in the UK. Government figures show that the chemicals and pharmaceuticals sectors alone made up 1.9% of gross value added to the UK economy in 2011 (total value of chemicals and pharma ~ £27bn). This project will contribute to the increasing need for Advanced Materials in Healthcare Technologies: as noted in the recent EPSRC Materials Review "UK businesses that produce and process materials have a turnover of around £170bn pa, represent 15% of the country's GDP and have exports valued at ~£50bn. A real opportunity exists for the UK in developing materials designed for targeted applications, reducing lead times from discovery to market and focusing on sustainability." Pharmaceutical products are a vital part of any materials strategy, and the polymer-based implant cancer drug, Zoladex, is a key indicator of the need for continuing investment in biomedical materials. AstraZeneca have invested £120 million in a new facility at Macclesfield, UK plant to meet continuing global demand for Zoladex, which is one of the world's leading therapies for prostate cancer and is also indicated for breast cancer. It is currently AstraZeneca's fifth largest selling drug with annual sales of ~ $1 billion.
The Fellowship is informed throughout by a strong link to AstraZeneca, who will provide expertise and guidance on how to take a lab-based formulation towards a marketable and manufacturable product. The costs of a potential new breast cancer formulation will thus be evaluated against the existing best practice, and the potential for meeting a currently intractable medical need.

Publications

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Bennett M (2020) Iron-Catalysed Radical Polymerisation by Living Bacteria in Angewandte Chemie

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Bennett MR (2020) Iron-Catalysed Radical Polymerisation by Living Bacteria. in Angewandte Chemie (International ed. in English)

 
Description We have already discovered that some materials for carrying drugs in the body can be made in a much 'cleaner' way than before and are pursuing IP opportunities in this area. We have discussed scale up with our partners AstraZeneca and will take a decision when the final in vivo results are in. We have some very promising initial data indicating that polymer architecture can be controlled with these syntheses and that in turn this enhances anti-cancer efficacy in an orthotopic in vivo model.
Our most recent data suggest that polymer structure also has a profound influence on residence time in the body, and that this in turn can be used to plan dosing schedules. In 2020 we published one paper describing refinement of 3D spheroid models and how novel redox-responsive materials travel through these cancer mimics, and 2 papers describing in vivo efficacy of polymers with 'designer' molecular architectures.
Exploitation Route Although we did not progress to full translation in the grant, we believe these materials may be useful not just for drug delivery, but also for biodegradable plastics in general. We are further considering how to develop this angle. We have new funded work with AstraZeneca in their iMed post-doc programme which has now started (see above) and we have made 3 applications to EPSRC and industry co-funded programmes to continue this work.
Sectors Chemicals,Construction,Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

URL https://onlinelibrary-wiley-com.ezproxy.nottingham.ac.uk/doi/full/10.1002/adhm.202000892
 
Description We have developed a deeper collaboration with AstraZeneca in the grant - leading to a shift in how we do the research. We met with scale-up and development specialists at AstraZeeca, and this resulted in us changing the project milestones such that we worked in a much more industry- and patient-focused way. We accelerated in vivo PK studies ahead of some of the previously planned chemistries, so that we were able to make stop-go decisions much earlier. We developed better links with Breast Cancer Now, and have taken part in Breast Cancer Awareness week at Nottingham. As Principal Investigator on this grant I have also been appointed to the committee of the Nottingham Breast Cancer Research Centre and have taken part with patient groups as part of a workshop organised in the grant. Our findings have also contributed to new research in the brain tumour research area, as some of the materials we developed for this project have potential advantages for administration following post-surgical resection of cancerous tissue. This helped to win an award from the 'Little Princess Trust/Children's Cancer and Leukaemia Group' worth £676k, led by a brain tumour surgeon, Stuart Smith, and a geneticist, Dr Ruman Rahman, at Nottingham.
First Year Of Impact 2019
Sector Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Appointment to EPSRC Big Ideas Advisory Group
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://epsrc.ukri.org/newsevents/news/theworldneedsbigideas/
 
Description Appointment to the EPSRC Science Engineering and Technology Board
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL https://epsrc.ukri.org/newsevents/news/members-recruited-to-the-epsrc-science-engineering-and-techno...
 
Description Affinity Polymers. Cameron Alexander Project Lead, Jonathan Ball (Co-I), Morgan Alexander (Co-I)
Amount £543,284 (GBP)
Organisation Merck 
Department MilliporeSigma
Sector Private
Country United States
Start 04/2018 
End 05/2019
 
Description AstraZeneca iMED PostDoc Project. Distribution and cargo release profiles of dendrimer-based nanocarrier formulations, designed for inhaled delivery of oligonucleotides.
Amount £350,000 (GBP)
Funding ID AZ iMED 744 
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 01/2020 
End 12/2022
 
Description Experiencing the micro-world - a cell's perspective
Amount £600,755 (GBP)
Funding ID EP/R035563/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 07/2018 
End 11/2021
 
Description Exploitation of a novel fungicide for preventing fungal contamination and deterioration of products and materials
Amount £200,561 (GBP)
Funding ID BB/P02369X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2017 
End 07/2019
 
Description Future Vaccine Manufacturing Hub: Advancing the manufacture and deployment of cost effective vaccines
Amount £9,947,570 (GBP)
Funding ID EP/R013764/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 12/2017 
End 03/2021
 
Description High resolution, cryogenic analytical and transfer scanning electron microscope (HR-CAT-SEM)
Amount £1,564,542 (GBP)
Funding ID EP/S021434/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 04/2019 
End 03/2024
 
Description Royal Society International Exchange Award - New Neuroprotective Therapies
Amount £12,000 (GBP)
Funding ID IES\R2\192256 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2020 
End 01/2022
 
Description "Materials for Virus Binding and RNA Vaccine Formations". Medilink East Midlands Virtual Seminar 25th June 2020. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Invited seminar to East Midlands regional SME showcase. The event resulted in a number of questions, and follow-up from 2 companies active in the East Midlands, and also a company based in Cambridge. Confidential discussions have taken place with 2 companies, with 1 Innovate Smart grant submitted and a KTP in planning.
Year(s) Of Engagement Activity 2020
URL https://www.medilinkem.com/event/webinar-materials-for-virus-binding-and-rna-vaccine-formations/
 
Description Invited talk at Wollaton Science Club 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Roughly 60 members of the public attended my talk at the Wollaton Science Club on "Plastcis - will they Destroy or Save the World?" The talk generated many questions, and the Science Club have indicated that they will invite future speakers and promote the work of the University further as a result.
Year(s) Of Engagement Activity 2020
 
Description Participation in "Wonder" - University of Nottingham public engagement festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Wonder is a large-scale event at the University of Nottingham and multiple teams display their work, primarily in research. I contributed to the Biomaterials Discovery team exhibit, which was visited by several hundred people throughout the day. Many expressed surprise that polymers were used so widely in medicine, and multiple comments indicated a change in attitude of some members of the public towards 'plastics'
Year(s) Of Engagement Activity 2017
 
Description • University of Nottingham Science Public Lecture: From cancer vaccines to Covid-19 and back - why vaccines for the pandemic may benefit future cancer patients" - December 17th 2020 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This was a Public Science Lecture in the University of Nottingham series. Perhaps because of the subject matter (vaccines....) this was the best attended lecture for many years, with over 250 individual log-ins and likely many more watchers.
There were multiple questions, particularly about RNA vaccines, and a number of participants said they were reassured about vaccines and were more likely to be vaccinated as a result. Whether this has translated into actual vaccine take-up isn't known, but the questions indicated an informed but also highly questioning audience.
This was a really rewarding event to do - and I will undoubtedly do more as a result.
Year(s) Of Engagement Activity 2020
URL https://mediaspace.nottingham.ac.uk/media/t/1_cnghpvyw