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PET Imaging in Drug Design and Development

Periodic Reporting for period 2 - PET3D (PET Imaging in Drug Design and Development)

Reporting period: 2018-06-01 to 2020-05-31

There is a current shortage in Europe of scientists who can use special imaging tools such as Positron Emission Tomography (PET) that could speed up and reduce the cost of development of life-saving drugs. This represents a significant problem as PET imaging plays a key role in cancer, heart conditions and neurological diseases and is used by all the major pharmaceutical companies to identify effective drugs at a much earlier stage of drug development. Currently, only 10 in 10,000 drug candidates that enter pre-clinical testing progress to human testing, and only 1 out of those 10 molecules actually make it to the market. The failure of many of these molecules in Phase III, as opposed to Phase I and II trials, means that a lot of resources are wasted getting to Phase III, only then to fail.
PET is a non-invasive and highly sensitive imaging technology developed to visualise and quantify biochemical and physiological processes in vivo. PET imaging can be used to address key questions such as what and where is the disease? Is the disease accurately targeted by the therapy? Is the treatment effective? The ability to answer these questions using PET imaging places scientists in a much more informed position to progress from pre-clinical testing to human testing, i.e. Phase III in drug development.
The four-year research programme PET3D (PET imaging in Drug Design and Development) has trained 15 Early Stage Researchers (ESRs) to become experts in PET, equipping them with the skills necessary to be able to apply PET imaging in an innovative way as a key technology for boosting cost effective drug design and development. We have brought together leading expertise from 6 European academic PET centres and 2 industrial organisations. Through regular network meetings and training schools each ESR has been provided with a holistic and exceptionally fertile research and training environment. The entrepreneurial experience of the ESRs has been also developed through secondments with our industrial beneficiaries and meetings with private-sector experts. The PET3D consortium successfully stimulated cross-fertilisation between the 15 different research projects, which shared the same overall challenges in PET imaging technology. Thus, while the research work in PET3D has been following 15 different research streams, together they formed a single body of research. This research endeavour has significantly contributed to the validation of PET imaging as a paradigm-changing tool in drug design and development. The research output of the PET3D project consisted of a vast and diverse set of deliverables, from the development of novel PET tracers as candidate diagnostics in oncology, cardiovascular and CNS disorders, to the establishment of novel nuclear imaging protocols for drug development, using a variety of molecular formats (small molecules, nanoparticles, proteins and antibodies).
The PET3D consortium was articulated in two main sections: (i) the scientific programme and (ii) the training programme. The activities programme was structured around five work scientific workpackages (WP 1-5) and one network-wide training and dissemination WP (WP 6). Each Scientific WP reflected a research theme and each WP involved 3 ESR-interrelated PhD projects.
The focus of WPs 1-3 was tracers in oncology, WP 4 was in the cardiovascular area and WP 5 was focused on the central nervous system (CNS).
To use PET to visualise biological processes in the body, various novel ‘tracer’ molecules need to be developed. These ‘tracer’ molecules should function in exactly the same way as the parent non-radioactive drugs or bioactive molecules but the difference is that they can be visualised in the body using PET.
WP4 involved the development of novel PET candidates that would be instrumental in detecting early heart failure and monitoring therapy. Finally, WP5 was centred on CNS pathologies such as ischemia and brain tumours (i.e. gliomas) in which PET tracers are required to cross the blood-brain-barrier.
ESRs have contributed to further develop PET imaging as a key technology in early stage drug development, in areas such as tracer development, novel radiochemistry methods and have contributed many different scientific advances in preclinical imaging. These achievements are essential to pave the way for the clinical development. To name a few examples, one of the small molecule tracers, [11C]osimertinib, that was developed is currently being used for clinical research in non-small cell lung cancer patients at the Amsterdam UMC. A nanobody targeting agent – scheduled to later undergo clinical trials - was developed to be able to detect tumor cells resistant to the immune system. Therapy effects were studied in brain cancer models using a new combination of radiotracers and different imaging modalities. The results showed that it is possible to visualise tumour growth and the infiltration of immune cells into the tumour area as well as modifications caused by chemo- and immune-therapy. Novel small molecules and antibody tracers for imaging atherosclerosis have been developed and preclinically validated. These findings are of high importance for future clinical applications to improve the treatment options for patients.

WP6 involved network-wide training and dissemination. The strength of the consortium enabled 7 international network training events to be held, which included a 5 day school on Radiopharmaceutical development at VUMC, Amsterdam and a 2 day school on Radiopharmaceuticals in drug discovery at the AstraZeneca site in Molndal, which also provided an overview of the drug discovery and development process and a site tour. A 1 day training workshop was held at CIC-bioMAGUNE, San Sebastian, this covered complementary and transferrable skills and addressed ‘life after PET3D’ providing talks on writing grant applications and creating a biotech company. All ESRs have disseminated their scientific results at a total of 73 external conferences and workshops in the form or posters or oral communications. So far there are 13 peer reviewed publications, 6 articles submitted awaiting review and 8 articles in progress. We also have one scientific review and one Impact article in non-specialised press, a radio interview, 2 short videos and an Instagram link as listed on the PET3D website (https://www.pet3d.eu/).
The primary aim of the PET3D project was to promote PET in Europe by training a new generation of PET imaging scientists. This aim was fully and successfully achieved. In particular, the PET3D programme exposed the ESRs to a multidisciplinary and inter-sectorial environment, making the researchers’ future careers more attractive thanks to the synergistic interplay between academia and industry. Three of the 5 ESRs that have received their PhD’s, have already moved on to research positions, one employed as a University Postdoctoral fellow, one as a Senior Research Scientist in Isotope Chemistry at AstraZeneca and one starting as an intern at a pharmaceutical company in Parma. 4 ESRs will be submitting their PhD thesis August 2020 and one has already secured funding to further exploit the research as a Postdoctoral fellow. 5 ESRs have their 3 year PET3D PhD research further extended through their Universities’ funding and will submit their PhD in their 4th year. Two patents have also been secured by the project.
ESRs involved in PET3D
Beneficiaries involved in PET3D
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