A major advance in understanding of the role of a key tumour suppressor gene, PTEN, in regulating tumour cell growth has provided valuable insights for potential future cancer treatment – thanks to a highly productive, long-term collaboration between scientists at AstraZeneca and the Signalling Laboratory of the Babraham Institute, Cambridge.
The new findings, published this week in Molecular Cell, help to explain why loss of the PTEN gene in people with prostate and some breast cancers is so important. These findings may help identify patients most likely to respond to a new generation of targeted therapies.
“Over 40% of prostate cancers lose PTEN and some lose both PTEN and another tumour suppressor gene, INPP4B, but we didn’t previously have a clear picture of how this affects tumour growth,” says IMED Biotech Unit scientist Sabina Cosulich, at AstraZeneca. “The new discovery has given us an important link between the biochemical function of PTEN and its role in prostate cancer, and in some triple negative breast tumours for which treatment is currently limited.”
The research brought together the complementary skills of the world-leading Babraham Institute molecular signalling group led by Dr Phill Hawkins and Dr Len Stephens and the oncology translational science expertise of IMED scientists.
Two research teams, one goal
By modifying previous techniques, the Babraham Institute scientists revealed that PTEN suppresses tumour growth not through one mechanism as previously thought, but two. They showed that, within the PI3K cell signalling pathway, PTEN regulates production of two lipid messengers. These are needed for activation of AKT – a protein that mediates cell growth and is a target for novel anti-cancer drugs.
We were really surprised that loss of PTEN caused such a dramatic increase in PI(3,4)P2 in our mouse model of prostate cancer. PI(3,4)P2 has generally been a bit of an enigma, with most scientists unsure of whether it acts merely as a degradation product of the accepted messenger molecule ‘PI(3,45)P3’, or it acts as an additional messenger in its own right. Recently however, several studies have provided compelling evidence that PI(3,4)P2 may actually regulate important components of cell growth and invasion. Therefore, our work suggests that studying some of these basic PI(3,4)P2-regulated processes may help us to understand why PTEN is such a powerful tumour suppressor and may also help us to identify new therapeutic targets in PTEN-mutated cancers
Using human prostate and breast cell lines, some with and some without PTEN, the IMED scientists validated the Babraham Institute findings, confirming the effects of PTEN on lipid messenger levels. They also contributed gene expression, metabolomics and RNA profiling data from a genetically engineered, PTEN deleted, prostate cancer model to corroborate subsequent studies by the Babraham Institute team.
“The joint data emphasised the importance of AKT as a target for cancer treatment, and the potential of the PI(3,4)P2 lipid messenger for helping to identify other drug targets, especially in patients whose tumours have lost PTEN and INPP4B,” says Dr Cosulich.
Applying the science
AstraZeneca has an AKT inhibitor in development, with accompanying research into diagnostic tests for PTEN and other biomarkers intended to aid identification of patients more likely to benefit from treatment.
Other potential medicines targeting different steps in PI3K signalling are at various stages of development. But, as Dr Cosulich concludes, the Cambridge collaboration offers a winning formula for ongoing research:
“Having such an open collaboration was essential for addressing a scientific puzzle of great significance to cancer research. Our team members are in regular contact and frequently work alongside each other. Hearing about the lipid biochemistry research from the Babraham Institute team and realising how we could translate its potential from an oncology perspective was a great moment for all of us!”