Radionuclide and ultrasound imaging of effective molecular radionuclide therapies and combination therapies in neuroendocrine tumours.

Neuroendocrine tumours (NETs) are rare but poor response to chemotherapies results in a <30% 5-year survival rates. Approval of beta particle-emitting [177Lu]Lu-DOTATATE, which binds somatostatin receptor 2A (SSTR2A) on NET cells, has been monumental for treating patients with advanced midgut NETs. However, complete remission remains rare. It is therefore necessary to find alternatives or effective combination therapies. 212Pb is a beta and alpha particle-emitter. A 212Pb version of [177Lu]Lu-DOTATATE, [212Pb]Pb-VMT-alpha-NET proved reduced NET tumour growth in some mice. The availability of photon-emitting imaging counterpart [203Pb]Pb-VMT-alpha-NET, could aid future theranostic approaches. Separately, we showed that treatment of NET cells with hydroxyurea or chemotherapeutic 5-fluorouracil increased SSTR expression, leading to enhanced cellular uptake of [177Lu]Lu-DOTATATE. Also, it has been shown that ultrasound can image oxygen bubbles created by local hydrogen peroxide injection in breast tumours (doi.org/10.1016/j.ijrobp.2020.06.022. We hypothesise ultrasound may also pick up the conversion of hydrolysed water species into oxygen bubbles after irradiation by our radionuclides. Aims: 1. create successful combination therapies of [212Pb]Pb-VMT-alpha-NET in vitro (2D and 3D) and in vivo 2. determine potential of [203Pb]Pb-VMT-alpha-NET to predict efficacy of combination therapies 3. determine sensitivity and ability of ultrasound to visualise radionuclide decay Techniques: 2D and 3D cell culture, animal studies, preclinical SPECT/CT and ultrasound imaging, radio-chemistry and biology. Objectives: Year 1: create and test radiopharmaceuticals for toxicity in cells (2D), set up 3D models Year 2: 3D radiotoxicity combination studies, combination studies with chemotherapeutics Year 3: preclinical therapy studies, ultrasound imaging work Year 4: preclinical imaging and therapy studies