Dr John Marshall at the BCI's Centre for Tumour Biology has received a highly competitive Cancer Research UK Drug Discovery Award grant. In fact his was the only grant awarded in the current round. The award will fund the refinement of a promising cancer targeting agent in collaboration with Professor Margaret Brimble, a medicinal chemist at the University of Auckland, New Zealand.
"I am delighted and feel privileged to have received this grant and am very excited to start work with Prof Brimble as soon as possible. I believe that we can develop an effective drug delivery system to target a variety of aggressive forms of cancer."
Dr Marshall's work for many years has centred on integrins, which are a type of cell surface protein that allow cells to stick to and "talk" to their environment. The messages the cells receive back from the environment then determine their behaviour. For the last 15 years he has studied a particular integrin called αvβ6 and has shown that it is found at high levels in cancerous tissue, but not on normal cells. Such molecules are referred to as biomarkers.
This 3D image of A20FMDV2 is the product of research by Dr Marshall's collaborator Dr Mark Howard, Head of NMR at the University of Kent, Canterbury.
Biomarkers are sought-after by researchers, as they present opportunities for targeting cancer cells while leaving normal tissue unharmed; a common problem with current chemotherapies is that they are not selective enough and therefore can cause unpleasant side-effects.
It is estimated that over 100,000 new tumours diagnosed each year are likely to be αvβ6-positive. Currently there is only one therapy being developed to target this integrin in cancer; an antibody that binds to and blocks the function of αvβ6.
Dr Marshall's group, however, are working on a small peptide (a tiny fragment of a protein) called A20FMDV2. When A20FMDV2 binds to αvβ6 it is quickly internalised into the cell; combining the cancer-specific nature of the integrin with this property, we have a promising therapeutic strategy.
It could be thought of as a Trojan horse; a cytotoxic agent (a small molecule that can kill cancer cells) piggybacks on the peptide carrier to gain entry into the cell, where it then destroys it from within. The cell will bring in the peptide because it doesn't recognise the danger. Collaborative efforts with the London University spin-out company to develop this kind of peptide-therapeutic have so far produced promising results.
Currently A20FMDV2 is very unstable in blood and is lost entirely from the blood in a short time, in part due to being broken down by proteases - enzymes that break down proteins. The aim of Dr Marshall and Professor Brimble's collaborative work is to redesign the peptide so that it avoids these attacks and persists in the blood long enough to penetrate deep into tumours. As a small molecule it has this advantage over large antibodies, which are often too big to get through tiny tumour blood vessels and diffuse all the way through tissues.
A375P melanoma cells engineered to either have or not have αvβ6. Internalisation of A20FMDV2 in green can be seen here over time in the αvβ6-positive cells.
"Our peptide synthesis group is really looking forward to working with Dr Marshall's world renowned tumour biology group. It is an honour to be able to contribute to such an exciting project that has a real need for the development of stable peptide mimics. A truly global collaborative effort is about to start: successive rounds of Professor Brimble's modified peptide designs, shipping them to the UK from New Zealand, Dr Marshall's lab testing them here at the BCI and then feeding back results to inform the next design steps.
The original A20FMDV2's short lifespan does however mean that it can also be used as an effective cancer imaging agent; since it binds to cancer cells, tagging it with a radio-active molecule that can be "seen" by PET or SPECT scanners, for example, means we can non-invasively see how much αvβ6 is on tumours and monitor treatment effectiveness over time. The A20FMDV2 imaging project, which includes work with a large pharmaceutical company, runs in parallel to the anti-cancer development angle - a strategy known as companion diagnostics in pharmacology.
This exciting project could lead to better treatment options for some cancer types that, at present, are very difficult to manage and have a poor survival rate, including pancreatic, oesophageal and lung cancer.