Development of next-generation anti-cancer radiopharmaceuticals
Lead supervisor: Professor Katherine Vallis
Co-supervisor: Professor Ester Hammond
Commercial partner: Blue Earth Therapeutics Ltd
The central goal of this project is to develop new radiotheranostic agents to image and treat cancer, with an initial emphasis on prostate and breast cancer. Molecular imaging plays an important role in cancer medicine: in the selection of patients for precision oncology treatments and in monitoring response to treatment. Effective new radionuclide therapeutics have been introduced in the management of prostate cancer and other malignancies in recent years. The project will focus initially on cell-surface nucleolin (NCL) as a putative target for radiotheranostics, but other internalising molecular targets will be explored. NCL is a a major constituent of the nucleolus and contributes to tumour growth, metastasis and drug resistance. We have recently confirmed that NCL is overexpressed at the plasma membrane in a panel of cancer cell lines in comparison to relevant non-malignant cells. The role of NCL at the cell surface is ill understood but it is known that on ligand binding NCL internalises, which would promote retention of radiolabelled ligands.
In preliminary work collaborators at the Rosalind Franklin Institute Nanobodies Discovery Platform have generated a nanobody (single chain camelid antibody) against human NCL which will act as a prototypic carrier molecule. Other antibody formats and peptide binders of NCL and other selected internalising molecular targets will be evaluated. (1) The first objective will be to investigate the specificity and binding characteristics of carrier molecules in cells that express the target at the cell surface versus those that do not or in which the target has been knocked down, using a range of approaches including confocal fluorescence microscopy, live cell imaging, flow cytometry and competitive binding assays. (2) In addition to antibody-based vehicles for targeting NCL or other targets, the project will include a peptide screen using a phage display approach to identify peptide binders to cell surface displayed target. (3) Protocols will be developed for radiolabelling of candidate carrier molecules with imaging and therapeutic radionuclides, and in vitro experiments performed to confirm retained binding properties. (4) The project will involve in vivo investigations to test the biodistribution and pharmacokinetics of candidate radiolabelled target-binders in molecular imaging (PET- or SPECT-CT) and tumour growth inhibition studies in appropriate xenograft, syngeneic and orthotopic models.
The benefit of the project to the industry partner is that they will engage with researchers at their local University whose goal is to identify new targets for radiotheranostics, and through them will access state-of-the-art preclinical research facilities. The researchers will benefit from interaction with a company that has successfully taken products from the academic setting into clinical trials and therefore has vast experience of translation of science from bench to bedside. The project is in line with the MRC’s strategic priority of research to accelerate the translation of discoveries into new treatments.
The project will generate new knowledge about the role of cell surface expression of NCL in cancer, lead to the discovery of high affinity target-binding molecules and will provide preclinical evidence regarding the suitability of the studied targets for radiotheranostics.
Apply using course: DPhil in Oncology
