Student: Paul Gape
1st Supervisor: Samantha Terry, King’s College London
2nd Supervisor: Graeme Stasiuk , King’s College London
Clinical Supervisor: Dr Lefteris Livieratos, King’s College London
Industry Supervisor: Prof Michael Schultz, Viewpoint Molecular Targeting
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/background:
This project would best suit a biochemist/biologist.
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.
