MICA: Radiobiology for effective alpha particle and Auger electron molecular radionuclide therapy in neuroendocrine cancer

Every two minutes, someone in the UK is diagnosed with cancer. The focus here is on neuroendocrine cancer, which begins in hormone-releasing neuroendocrine cells and can occur anywhere in the body including the lungs, appendix, small intestine, rectum and pancreas. Although rare, they are very hard to treat; there is therefore a need for novel options to treat both the original tumour and cancer cells that have spread throughout the body.

This will be addressed by us creating new injectable, radioactive drugs that specifically home to cancer cells anywhere in the body. The radioactive compounds investigated here use gallium-67 and thallium-201 attached to DOTATATE, which delivers the radioactivity to neuroendocrine cancer cells. Gallium-67 and thallium-201 both release short-distance, high energy Auger electrons. These only irradiate cells to which they are attached and are available with ease. The project will also use lead-212, as it too emits radiation at a high energy across a short distance (alpha particles). This is needed to kill singular cancer cells. But lead-212 also simultaneously releases beta particles that are useful when treating tumour spheres. Unlike other alpha particle-emitters, lead-212 can crucially be obtained at quantities needed for a feasible, sustainable therapy in the clinic. We are working with a company that has produced radioactive lead-labeled peptides (203Pb- and 212Pb-VMT-alpha-NET) for imaging and therapy of neuroendocrine tumours.

We will then carry out studies in neuroendocrine cancer cells grown in the lab in layers and as spheres, to better mimic a tumour, as well as in animal models of neuroendocrine cancer. These studies will allow us to understand the relationship between radiation dose delivered and damage to tumour cells as well as healthy kidney cells. This, alongside computer modelling, will inform future clinical trials in terms of required and prescribed injected amounts of radioactive compounds for effective tumour killing at levels that do not damage healthy tissues such as the kidneys.

Finally, studies will be carried out to ascertain how effective the radioactive compounds are in killing cancer cells that have been pretreated with chemotherapies. Hopefully, we will show that combining chemotherapies with the radioactive compounds increases the overall tumour killing ability and work out how this is achieved.

Through this work, we will have advanced the radiobiological understanding not only of forms of radioactivity that are high in energy and short in distance, such as 67Ga- and 201Tl-DOTATATE and 212Pb-VMT-alpha-NET but of Auger electron and alpha particle-emitters in cancer models in general. Our research will also guide further work with other forms of radioactivity that have therapeutic potential.

Improvement of treatment remains a priority as 28% of UK deaths are attributable to cancer. Neuroendocrine tumours (NETs) are the exemplar cancer type in this proposal. Whilst rare (>4,000 novel UK diagnoses annually), NETs occur anywhere in the body. External beam radiotherapy and molecular radionuclide therapy in the form of 177Lu-DOTATATE have enhanced survival for some NET patients, but the long-term outlook for most patients with advanced NETs remains poor.

Here, we will create new molecular radionuclide therapies targeting somatostatin receptors on NETs by incorporating high linear energy radionuclides emitting Auger electrons (67Ga- or 201Tl-DOTATATE) or alpha particles (212Pb-VMT-alpha-NET). These will be characterised (radio)chemically and for target specificity and localisation within a cell or spheroid. Various 2D ad 3D NET cell models will be used. Studies will compare DNA damage and cell killing induced by the radiopharmaceuticals with 177Lu-DOTATATE and X-rays and relate these to cell and nuclear absorbed radiation dose. Radiopharmaceutical toxicity will also be measured in healthy kidney cell lines.

In vivo SPECT/CT imaging and ex vivo biodistribution studies will enable whole body and tumour dosimetry. Therapy studies with 212Pb-VMT-alpha-NET in AR42J NET tumour-bearing mice will also be carried out either as a single injection of 3.7 MBq or fractionated across several injections at 3 x 1.2 MBq, depending on dosimetry outcomes. Kidney toxicity will be determined by immunohistochemistry. This, alongside in silico modelling will inform future clinical trials in terms of required and prescribed injected amounts of radioactive compounds for effective tumour killing at levels that do not damage healthy tissues such as the kidneys.

Finally, further in vitro studies will ascertain whether 212Pb-VMT-alpha-NET effectiveness is enhanced using chemotherapeutic drugs, e.g. 5FU, by increasing somatostatin receptor expression on NET cells.