Student: Barbara Dworakowska
1st Supervisor: Eric Aboagye, Imperial College London
2nd Supervisor: Ran Yan, King’s College London
Clinical Champion: Tara Barwick, Imperial College London
Industry Supervisor: Peter Iveson
Additional Supervisor: Louis Allott, Imperial College
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 / Background:
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 (emits longer path-length β-particles of 0.8 mm suitable for killing distant tumour cells) and iodine-125 (emits low-energy Auger-particles across a short path-length of 0.06–17 μm) 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 α-particle emitters but with limited systemic toxicity. Thus, the [125/131I]-NLF-LINKER-bAG-TOCA pair (Fig. 1) 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 (βAG-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.
The candidate should have strong background in organic synthesis with some experience in pharmaceutical development.
Smart cell nuclear-localising 125/131I-labelled octreotates for sandwiched beta- and Auger-particle therapy of metastatic neuroendocrine tumours would allow for dose modulation, maximising their therapeutic efficacy and minimizing toxicity.