Smart cell nuclear-localising 125/131I-labelled octreotates for sandwiched beta- and Auger-particle therapy of metastatic neuroendocrine tumours

Aim of the PhD Project:
Develop a library of 125/131I-labelled octreotate pairs that can selectively accumulate in the neuroendocrine tumour (NET) cell nuclei;
Demonstrate that the tandem use of the optimal cell nuclear-localising 125/131I-labelled octreotate pair emitting beta-particles and Auger-particles is superior to the conventional [177Lu]DOTATATE in NET peptide receptor radionuclide therapy.
Project Description
Lutathera ([177Lu]DOTATATE) has become the standard treatment of somatostatin receptor type 2-expressing (SSTR2) neuroendocrine tumour (NET) patients. The NETTER-1 Phase III trial showed that Lutathera prolongs progression free survival (PFS) in metastatic NETs, although objective response rate is low (18%). Our analysis shows that PFS to Lutathera is superior in patients showing partial response compared to stable disease. Most patients on Lutathera only achieve stable disease; together with long therapy duration and high cost. Thus, more efficacious therapies are needed.
A major limitation of current radiometal-based peptide receptor radionuclide therapy (PRRT) for NETs is renal toxicity compromising achievable therapeutic effectiveness, with severe (CTC grade 4-5) nephrotoxicity occurring in up to 14% of cases. Nephrotoxicity results from residualisation of radiometals in kidney cells, a property that is not associated with radioiodines. While concomitant infusion of positively charged amino acids can decrease renal toxicity, they can also accentuate nausea and vomiting. Transient bone marrow toxicity is another important side-effect of beta-emitting-PRRT.
Efficacy of PRRT depends on the radionuclides decay characteristics. Despite this knowledge,there has beenlittle consideration to tailoring PRRTs to tumour burden/size. Tandem or sequential injection of [177Lu]DOTATATE and [90Y]DOTATATE (both of which emit beta-particles over a long path-length), considers differential tumour burden response, and improves efficacy. The more practical 131I/125I pair has not been studied, perhaps due to challenges in chemical accessibility and implementing facile radiochemistry to produce radioiodinated octreotates that are resistant to deiodination. We hypothesise that sandwiched PRRT with iodine-131 and iodine-125 will efficiently target both large tumours where radiotherapeutic delivery may be heterogeneous, and small micrometastases before dose-limiting toxicity is reached. This approach will allow for tailoring therapy to an individual patient's NET status with limited toxicity. Effective tumour cell killing with short path-length 125I requires the radioisotope to be spatially localised close to the nucleus. This would be achieved by using a thiol or acid sensitive linker to conjugate a radioiodinated nuclear-localising functionality (NLF) to octreotate. It is expected that following SSTR2-dependent cellular internalisation, the increased intracellular free thiol concentration or lysosomal acidity will cleave the corresponding linker and release the radioiodinated NLF which will subsequently accumulate in the cell nucleus. The disintegration of iodine-125 close to DNA will be densely ionising and elicit therapeutic effectiveness comparable to high linear energy transfer radiation alpha-particle emitters but with limited systemic toxicity. Thus, the [125/131I]-NLF-LINKER-bAG-TOCA pair with enhanced cell nuclear-localising ability provides a practical solution to achieve high therapeutic-index sandwiched PRRT. The [125/131I]-NLF-LINKER-bAG-TOCApair would be radiosynthesized via identical methods, which simplifies the clinical implementation of this strategy. The structural modifications to the octreotate core (bAG-TOCA) may strongly influence in vivo pharmacokinetics of the proposed peptides. Thus, we will prepare the positron emitting, [124I]-NLF-LINKER-bAG-TOCAs and use PET to investigate their pharmacokinetics.

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.