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New drug target leaves lung cancer cells alone and dying


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New drug target leaves lung cancer cells alone, lonely and dying

By Mike Nagle

02/01/2008- It seems even tumour cells can get lonely; scientists have discovered that by cutting off a key gene, lung cancer tumour cells are left 'homeless' and they can't survive on their own.

The gene in question is called 14-3-3zeta and it can now be considered a potential target for selective anticancer drugs, according to Professor Haian Fu at the Emory University School of Medicine. These latest research results were published in the 24 December edition of the Proceedings of the National Academy of Sciences (PNAS).

Lung cancer kills more Americans annually than any other type of cancer, according to the National Cancer Institute. Yet treatment options are very limited.

"The recent trend towards targeted therapies requires us to understand the altered signalling pathways in the cell that allow cancer to develop," said Prof. Fu.

"If you think about genes that are deregulated in cancer as drivers or passengers, we want to find the drivers and then, aim for these drivers during drug discovery."

Prof. Fu and his collaborator, Dr Fadlo Khuri, deputy director of clinical and translational research at Emory Winship Cancer Institute, chose to focus on the gene 14-3-3zeta because it is activated in many lung tumours. In addition, recent research elsewhere shows that lung cancer patients are less likely to survive if the gene is on overdrive in their tumours, Dr. Fu explained.

There are seven 14-3-3 genes, each designated with a Greek letter. Their protein products act as adaptors that can clamp onto other proteins, depending on whether the target protein has been phosphorylated or not. One of the pathways 14-3-3 helps control is epidermal growth factor receptor (EGFR) signalling, which drives the growth of lung cancer.

The team of scientists, including lead author Dr Zenggang Li, used RNA interference (RNAi) to selectively silence the 14-3-3zeta gene. They found that when 14-3-3zeta is turned off, lung cancer cells become less able to form new tumour colonies in a laboratory test.

One of the most important properties of cancer cells is their ability to grow and survive without touching other cells or the polymers that connect them. The researchers found that if they turned 14-3-3zeta off, the tumour cells once again become vulnerable to anoikis (Greek for homelessness), a form of cell death that occurs when cells that are accustomed to growing in layers find themselves alone.

"You can see how control of anoikis means 14-3-3zeta could play a critical role in cancer invasion and metastasis," Dr. Fu says. "The mechanistic question we still haven't answered is: what makes zeta unique so that it can't be replaced by the others."

Further experiments also showed that 14-3-3zeta regulates the Bcl2 protein family, which is a popular target for cancer drug developers thanks to its role in cell death. If 14-3-3zeta is absent, it upsets the balance within the Bcl2 family.

The finding has implications beyond lung cancer, in that 14-3-3zeta is also activated in other forms of cancer such as breast and oral, he notes.

"Targeting this critical molecule could lead to meaningful therapeutic progress," said Dr Khuri.

Dr Fu and his co-workers are using a robot-driven screening programme at the Emory Chemical Biology Discovery Center to sort through thousands of chemicals that may disrupt its interactions specifically. They hope to identify these compounds rapidly and move them from bench into clinic testing to benefit patients.

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