PA12-12 Skerry Lay summary
Principal Investigator: Professor Tim Skerry, Professor of Orthopaedic
Biology and Head of Department at the School of Medicine, University of
Sheffield
Lay title:
RAMP-3 – a new target to prevent cancer spreading
What are you proposing?
We will determine how a new target implicated in spreading of prostate tumours (metastasis) affects
communication between cells in a tumour and communication between the tumour cells and the host tissues.
Why are you proposing it?
The communications between tumour cells are essential for the tumour to survive, for its cells to divide and
grow and for them to replicate. The communication between tumour and host is involved in the production of
new blood vessels that supply the tumour with nutrients and oxygen and potentially allow metastatic spread of
cells from the primary tumour to other sites. In the case of prostate cancer, it is these metastatic secondary
tumours that are the predominant cause of death. Our pilot experiments have shown that many tumour cells
have so called “accessory proteins” that alter the way that cells perceive chemical signals. One of these is
called RAMP3 and is present in many tumours. RAMP3 also helps the tumour to signal to host cells, hi-jacking
their systems to induce blood vessel growth to supply the tumour. RAMP3 also interacts with a protein called
LOXL2 that is known to be involved in the way tumours grow and spread.
We have shown in pilot studies that an antibody that we have made blocks RAMP3 signalling, slows prostate
tumour cell proliferation in culture, and when given to mice with breast or pancreatic tumour cell tissues
inserted, delays tumour growth. More remarkably, in separate studies, if prostate tumours are given to control
mice, they develop severe disease and die from metastases within 3 weeks. Mice lacking the gene for RAMP3
develop primary tumours but when the control mice are becoming sick and dying, they only have primary
tumours and no significant metastases. This suggests that RAMP3 is important in metastatic spread and
primary tumour growth.
How are you proposing to do it?
We will perform experiments to determine whether preventing RAMP3 signalling in tumour cells or in host cells
has effects that are different from prevention of LOXL2 activity. We will inject normal and RAMP3 knockout
mice with control prostate cancer cells and those engineered not to express RAMP3 or LOXL2 and assess
tumour growth, burden and spread analysing thin sections of the prostates, livers and lungs 3 weeks after
cancer cells have been injected. We will identify and measure bone metastases using a specialist X-ray
technique called microcomputed tomography - like a high resolution CAT scan.
How long will it take?
In total the work will take nine months.
Prostate Cancer UK is a registered charity in England and Wales (1005541) and in Scotland (SC039332). A company limited by guarantee registered number 2653887 (England and Wales).
What is the budget?
£49,978
Why is this project suitable for a pilot award?
A recent study shows that LOXL2 signalling (identified as a therapeutic target) is controlled by RAMP3, but this
is a new area, so we need to establish direct data to support subsequent studies focused on understanding
these mechanisms and developing anti-RAMP3 therapies in this developing field.
What are the expected outcomes?
We expect that there will be differences between primary tumour growth from normal cells and those lacking
RAMP3 and LOX2, and that in animals lacking RAMP3 there will be additional effects of reduced growth and
tumour metastasis.
How could it make a difference to the lives of men affected by prostate
cancer?
Because RAMP3 is not essential for life, it can be blocked without serious side effects common with
chemotherapy and radiotherapy. We believe an antibody or small molecule drug may be more effective and
better tolerated in preventing prostate tumour metastasis than current treatments.
Please write a summary of the project in one sentence only.
Pilot experiments suggest that if we block signalling between tumour and host involving a molecule called
RAMP3, there are dramatic benefits in prevention of prostate cancer metastasis: this project is to progress that
work to provide proof of principle for development of prostate cancer treatment,