Secrets of tumour-suppressing gene unravelled by scientists at Babraham Institute and AstraZeneca

Collaboration could help identify potential therapeutic targets for prostate and breast cancers.

Researchers in the Cambridge area have collaborated to address “a scientific puzzle of great significance to cancer research”.

Scientists at the Babraham Institute and AstraZeneca’s IMED Biotech Unit made the breakthrough in our understanding of an important tumour-suppressing gene called PTEN.

It is thought to be the second most commonly altered gene in human cancers.

They have learned how the gene may control cell growth and behaviour and how its loss contributes to the development of certain types of cancer.

The loss of PTEN has a major impact on many people with prostate cancer and those with some breast cancers, according to the study, led by Dr Len Stephens and Dr Phill Hawkins.

The gene typically slows the growth of cells by regulating the levels of a chemical - phosphatidylinositol-3,4,5-trisphosphate or PI(3,4,5)P3 - which helps to prevents cancer.

But the researchers learned that this was not the gene’s only method of preventing uncontrolled cell growth.

It also reduce the levels of a similar molecule - phosphatidylinositol-3,4-bisphosphate or PI(3,4)P2). The role of this molecule is still emerging but it is thought it may alter the activity of the AKT protein, which is a key regulator of cell growth. The molecule may also influence other proteins that control the process of invasion – in other words, how cancer cells spread through the body.

Dr Hawkins said the researchers were “really surprised” that the loss of this gene led to such a dramatic increase in the molecule, which has “generally been a bit of an enigma”.

He suggested that the work aids our understanding of “why PTEN is such a powerful tumour suppressor and may also help us to identify new therapeutic targets in PTEN-mutated cancers”.

Sabina Cosulich, of AstraZeneca’s IMED Biotech Unit, said: “Over 40 per cent 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.

“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 researchers studied human cancer cells and animal models of cancer in the lab.

They learned the loss of the gene, and resultant chemical change, can lead to the hyperactivation of AKT. This suggests AKT could be an effective target for new cancer treatments.

AstraZeneca has an AKT inhibitor in clinical trials for prostate, breast and other cancers.

The collaborative work, published in the journal Molecular Cell and featuring contributions from Akita University, Japan, and from GSK, could enable tests to be devised to identify patients who will benefit from such targeted therapies.

Dr Cosulich said: “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.”