Matrix metalloproteinases (MMPs) are a set of zinc-dependent endopeptidases with the capability of degrading all components of the extracellular matrix and basement membranes. Breakdown of the extracellular matrix (ECM) is crucial for the body’s normal function for processes such as embryonic development, morphogenesis, reproduction and tissue remodelling. The activity of MMPs within the body is generally under tight control but this can be disrupted. Overexpression of MMPs has been associated with a variety of diseases including rheumatoid arthritis, osteoarthritis, cardiovascular diseases such as atherosclerosis, and significantly cancer. Therefore, MMPs are targets for both imaging strategies as well as drug development.
In this project we aim to build on previous research carried out collaboratively between the Aboagye and Vilar groups to develop novel MMP-sensitive 68Ga-PET probes to image the early stages of cancer (Sheena Cowell PhD 2013; supervisors Profs Aboagye and Vilar). In particular we will target MMP-14, a membrane bound proteinase which is found on both tumour and stromal cells in a wide variety of cancers and has been considered as an early biomarker for invasive cancers. Recently, our groups have found a series of peptides (substrates) that are cleaved by MMP-14; we have found that the degradation of these peptides is most selective with MMP-14 as compared to, for example, MMP-9 and MMP-2. The MMP-14 substrate will be linked to a cell penetrating peptide which will only be ‘activated’ once this protease cleaves the substrate allowing for selective accumulation of the 68Ga-PET probe inside cancer cells with overexpression of MMP-14 (see scheme in next section). A second important aim of this project is to incorporate a cancer pro-drug (based on a platinum(IV) compound) to these MMP-sensitive 68Ga-PET probes. Upon cleavage of the peptide substrate by MMP-14, both the imaging (68Ga) and therapeutic (Pt) components of the theranostic probe will be internalised (thanks to the cell penetrating peptide) inside the cancer cells. The 68Ga complex will allow for the PET imaging to be carried out while the platinum(IV)-based prodrug will be activated once inside the cancer cell (see Scheme in next section).
A particular clinical indication area for these theranostic probes will be ovarian cancer where platinum based therapy is standard of care and where platinum resistance occurring from multiple mechanisms including reduced cellular uptake are prevalent in the recurrent setting. Thus, ovarian cancer models will be used. The Aboagye lab has expertise in the use of these models in vitro and in vivo.