Development, radiobiological assessment and dosimetry of radiopharmaceuticals emitting alpha and beta particles

Aim of the PhD Project:
Cancer recurrence is often related to the inability to treat small metastases as well as resistance to current available therapies.
To help overcome this issue, we will create new targeted molecular radionuclide therapeutics and imaging strategies in cancer using SPECT imaging and alpha/beta particle-emitting radionuclide lead-212.

Project description:
Key hypotheses are:

Novel cancer-targeting radiopharmaceuticals incorporating radioactive lead are stable and specific for their targets. (WP1)
Radiation cell and nuclear dose relate to toxicity by 212Pb-VMT-alpha-NET or other 212Pb-labelled radiopharmaceuticals in cancer cells. (WP2)
Radiation dose determined from 203Pb-VMT-alpha-NET SPECT/CT imaging relates to tumour growth inhibition by 212Pb-VMT-alpha-NET (WP3)
A biologically-informed in silico model can predict therapeutic efficacy of 212Pb-labelled radiopharmaceuticals (WP4).
Background:

Every two minutes, someone in the UK is diagnosed with cancer. While treatments are improving and cancer survival has doubled in the UK in the last 40 years, tumour resistance and metastasis remain significant challenges in cancer therapies. Neuroendocrine tumours (NETs) is the cancer type focussed on here. Once they metastasize, the 5-year survival rate drops to <30%, as they respond poorly to chemotherapies.

Molecular radionuclide therapy (MRT) is an exciting new way to overcome therapy resistance in primary cancer cells and simultaneously target metastases. MRT employs radioactivity attached to antibodies or peptides, injected into the blood stream to specifically target and irradiate cancer cells spread throughout the body. The field has been driven by beta particle-emitters, but alpha particles provide the possibility to go from palliation to curative therapy.

Despite their potential, a limited radionuclide supply and/or inconvenient or cumbersome radiochemistry for alpha particle-emitters such as 213Bi, 225Ac, 211At and 227Th, mean other avenues need to be explored. Equally, in-depth radiobiological studies need to be carried out (such as described here) to determine acceptable ratios of tumour:healthy tissue toxicity and accurate radiation dose limits to organs that are currently limiting the amount of activity that can be injected.

212Pb is fast gaining attention in MRT to treat both large primary tumours and small metastases, due to the release of beta particles and short-lived daughter alpha particles as well as its physical half-life and ability to be generator-produced. Also, this radionuclide enables a theranostic approach as 203Pb can be imaged by single photon emission computed tomography (SPECT) allowing the location and amount of 203Pb delivered to be determined. This allows targeted calibration of 212Pb delivery to a tumour. Initial (pre-)clinical work has shown the potential of 212Pb-labeled radiopharmaceuticals in treating a range of cancers with little toxicity.

Here, we will explore, optimise, and carry out radiobiological studies to maximise impact of a novel radionuclide therapy (212Pb-VMT-alpha-NET; produced by collaborator Viewpoint Molecular Targeting) for patients with neuroendocrine tumours as well as explore other cancer-targeting approaches. This will be achieved through MRT using not only somatostatin receptor-binding peptides (to target MRT to NETs), but also to other cancer-targeting moieties such as PSMA in prostate cancer, attached to radioactive alpha particle-emitter, 212Pb and to use the imaging equivalent (using 203Pb) to determine optimal delivery of 212Pb to cancer cells.

Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.

Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.

- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.

- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.

- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.

We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.