Title: A Chemical Toolbox for Targeted Radionuclide Imaging and Therapy of Cancer Cell Receptors
Funder: Cancer Research UK

Abstract: BACKGROUND Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) allow quantitative whole-body molecular imaging of cancer. One class of PET and SPECT molecular radiopharmaceuticals incorporates a radioactive metal bound via a chelator attached to a biomolecule, which targets tumour cell-surface receptors. Targeted Radionuclide Therapies can incorporate therapeutic radiometals into the same molecular architectures to deliver therapeutic radiation. These radiopharmaceuticals have provided patient benefit in clinics where they are available, however the complexity of their radiosynthesis is a barrier to population-wide availability. There is a pressing need for oncological molecular radiopharmaceuticals that can be easily and affordably synthesised to enable wider access to their benefits. Chelators that can be attached to receptor-targeted proteins and peptides, and rapidly and quantitatively bind radiometals under mild conditions will enable simple “kit-based” radiosynthesis of molecular radiopharmaceuticals. AIMS 1. Develop new versatile chelators as enabling technologies for routine one-step, kit-based preparations of molecular radiopharmaceuticals based on a range of radiometals; 2. Apply these chelator platforms to the evaluation of receptor-targeted PET, SPECT and therapeutic radiopharmaceuticals for new molecular targets, in particular, prostate specific membrane antigen (PSMA), over-expressed in prostate cancer; and human epidermal growth factor 3 (HER3) whose expression is associated with resistance to EGFR-inhibitor therapies in lung cancer. METHODS We will prepare new chelators that are simple to attach to biomolecules and simple to radiolabel. These will be with Ga-68 and Zr-89 (PET), Tc-99m (SPECT), and Bi-213/212, Pb-212 and Ac-225 (alpha-emitters). The chelators will be used to radiolabel: (i) PSMAt peptide for targeting PSMA in prostate cancer. This is a good candidate for clinical translation, and it will provide proof-of-principle in well-defined biological models. (ii) New HER3-targeted proteins developed in collaboration with CCIC researchers. The new imaging radiotracers will be used to elucidate upregulation and intratumoral heterogeneity of HER3 expression in NSCLC in response to EGFR-targeted tyrosine kinase inhibitor therapies. HOW THE RESULTS OF THIS RESEARCH WILL BE USED There are many new developments in biomolecules that target tumour cell-surface receptors. The easy-to-use chelator platforms developed here will enable rapid evaluation, validation and translation of the best biomolecules for PET/SPECT imaging and targeted radiotherapy of cancer. The new chelators will provide the nuclear medicine community with an alternative to complex radiosyntheses and expensive infrastructure. Simple, kit-based preparations of receptor-targeted radiopharmaceuticals will provide greater access to molecular radiopharmaceuticals, including those targeting PSMA and HER3, enabling more cancer patients to benefit.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS