PG12-16 Clarke Lay summary
Principal Investigator: Professor Alan Clarke, Professor at the Cardiff
School of Biosciences, Cardiff University
Lay title:
Exploring new molecular and cellular pathways to better define risk in prostate cancer.
What are you proposing?
We have two key aims; the first is to explore the importance of three key molecular pathways in prostate
cancer initiation and progression. Mutation within these pathways, termed the Wnt, PI3-kinase and Ras
pathways, is well recognised to underpin many different cancer types, and each pathway has been
independently linked to prostate cancer. Here, we wish to determine the extent of interplay between these
mutations with the aims of better understanding the mechanisms that cause tumours and better identifying
aggressive disease. The second aim is to investigate the possibility that prostate cancers are actually driven
by a subpopulation of cells, so termed ‘cancer stem cells’, and that the above pathways influence tumour
formation by altering this population of cells. We therefore wish to characterise the extent of this population
within tumours, and also determine the influence of each mutation on the size of this pool of cells.
Why are you proposing it?
The molecular basis underlying prostate cancer remains poorly understood. This is currently a key barrier to
the development of new therapies, as suitable new targets remain elusive. There are also significant difficulties
in treating aggressive disease, and indeed in identifying those tumours which are likely to progress to become
aggressive. Our studies will help clarify the interactions between three key pathways which we hope will open
new therapeutic possibilities and will also allow tumours to be profiled to better predict response to therapy
and risk of progression. We also wish to characterise the effect of these mutations on the supposed cancer
stem cell pool. The notion of the cancer stem cell derives from a series of experiments which have shown that
not all cells within a tumour have an equal capacity to ‘seed’ new tumours – indeed that there is a small
population of cells which are the key ‘drivers’ of tumour formation.
The extent of the cancer stem cell phenomenon remains debated. However, if correct, it has very important
implications for the way we view and treat disease. If, as we suspect, prostate tumours are actually driven by a
small group of cells within the tumour then the bulk response of the tumour to therapy may actually be
misleading. For example, therapies which are apparently successful because they initially shrink tumours may
actually be “bad” because they encourage expansion of the cancer stem cell population. This clearly has
important implications for how we treat disease and how we interpret response to therapy. The studies
proposed here are therefore aimed at exploring the accuracy of the cancer stem cell concept and determining
whether it is useful in predicting aggressiveness and response to therapy.
How are you proposing to do it?
We will use two basic approaches. The first will be to use state-of-the-art mouse models of human prostate
cancer to define the effects of pathway mutation on tumour initiation, progression, and the size of the
supposed cancer stem cell population. The second will be to use human tumour samples to profile both the
individual pathways and the cancer stem cell pool.
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).
How long will it take?
The project will be complete in three years
What is the budget?
£244,086
What are the expected outcomes?
We will establish the extent of interplay between mutations in PI3-kinase, Wnt and Ras pathways in both
prostate tumour initiation and progression. We will also define the effect of these mutations on the size of the
supposed cancer stem cell pool. Finally, we will analyse a series of 300 human prostate tumours to see if we
can use pathway status and the cancer stem cell profile to enhance our capacity to both assess risk and
identify aggressive disease.
How could it make a difference to the lives of men affected by prostate
cancer?
The project could have two key impacts. First it may identify a subpopulation of patients for whom targeted
therapy against the Wnt/Pi3-kinase/Ras pathways may represent a new therapeutic avenue. Second, it may
deliver a set of markers that will permit a much better risk stratification for patients with prostate cancer based
on pathway/cancer stem cell status.
Please write a summary of the project in one sentence only.
This project will explore the interplay between three key molecular pathways associated with prostate cancer;
in doing so it will reveal new markers of tumour aggressiveness and risk.