Joint Annual Research Report 2004 - The Royal Marsden

Extracellular
environment
Signal
Receptor PI3 kinase PIP 3 PKB
Figure 2.
The PI3 kinase/PKB
pathway.
Intracellular
environment
Cyclin D1
Proliferation
Other proteins
Survival
Plasma
membrane
of cell
a chemical, PIP3, that binds to and promotes activation
of PKB. Once active, PKB sends signals throughout the
cell via interactions with other proteins to promote both
proliferation and survival (Figure 2).
A key downstream target of PKB is a protein known
as cyclin D1, which is an important regulator of cell
proliferation and currently is under investigation in our
laboratory. PKB acts on proliferation by regulating the
amount of cyclin D1 in the cell (Figure 2). When PKB
is actively sending signals throughout the cell, the level
of cyclin D1 will increase, leading to uncontrolled cell
proliferation, as in cancer. When PKB is switched off,
the level of cyclin D1 in the cell will decrease and cell
proliferation will cease.
The PI3 kinase/PKB
pathway is a major
controller of cell
proliferation and
survival and it can
become misregulated
in cancer.
Overexpression of receptors that
relay signals in cells
In particular, the receptors that relay signals to the PI3
kinase/PKB pathway (see Figure 2) are overexpressed
in lung and breast cancer, whilst genetic alterations
that cause misregulation of PI3 kinase itself and the
chemical messenger it produces have been discovered
in colon, breast, prostate and ovarian cancer. PKB is
also overexpressed in a number of tumour types.
Overexpression of cyclin D1 is associated with a variety
of cancer types and contributes to the development of
cancer. For example, overexpression of cyclin D1 has
been associated with the development of breast cancer.
These discoveries have led us to initiate a major
programme to discover and develop inhibitors of PKB
for the treatment of cancer.
Inhibition of PKB may
have therapeutic value
in those tumours that
exhibit abnormalities of
the PI3 kinase pathway
or overexpression of
cyclin D1 protein.
Drug discovery and
development – a
multidisciplinary programme
Drug discovery and development require input and
expertise from a number of different disciplines,
including basic research, high throughput screening,
medicinal chemistry, all the way through to the planning
and implementation of clinical trials. The PKB
programme reflects this multidisciplinary approach,
involving a number of teams from the Cancer Research
UK Centre for Cancer Therapeutics and the Section of
25