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Scientists discover powerful new inhibitor of cancer stress signal

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Scientists have discovered a powerful new chemical inhibitor that blocks a crucial system used by cancer cells to cope with stress.

The new inhibitor – which isn’t yet a drug, but could be developed into one – knocks out a vital set of stress signals regulated by a master control molecule in cells called HSF1. It was able to kill human ovarian cancer cells grown in mice. 

The discovery is exciting because HSF1 signals are used by cancer cells across a range of tumour types to stay alive when exposed to stressful conditions, but up to now there have been no drugs capable of targeting it. 

The researchers, at The Institute of Cancer Research, London believe treatments to block HSF1 could be effective against many different cancers, including forms of ovarian cancer that are currently effectively untreatable. 

These findings come from a research programme funded by Cancer Research UK, the Cancer Research Technology (CRT) Pioneer Fund and the ICR. The new study is published in the Journal of Medicinal Chemistry.

A complex web

HSF1 controls a complex web of signals that are triggered in response to cellular stress.

It is not usually activated in normal cells – but some cancers become dependent on it to stay alive because cancer cells are in a constant state of stress, triggered by gene mutations and the strains of rapid cell division.

Researchers screened around 200,000 chemicals of different structures and sizes looking for any that blocked the production of an important signal controlled by HSF1, called heat shock protein 72, in cancer cells.

Among the hits was one containing a chemical motif called a bisamide. The researchers designed hundreds of new iterations of the bisamide, adding new chemical features, to generate a prototype drug which strongly inhibited HSF1 signalling. 

The new molecule, called CCT251236, is described by the researchers as a chemical probe, because it will enable researchers to precisely explore the effects on cancer cells of blocking HSF1 signalling. 

It could also lead scientists to a new drug capable of blocking cancer’s stress response that might prove effective against a variety of cancer types. 

Potential new avenue for treatment

The research team also discovered that the prototype drug binds to a molecule in the cell called pirin. 

Future studies will explore whether it is the molecule’s effect on pirin which is allowing it to block the HSF1 stress response pathway. 

As well as strongly inhibiting the growth of cancer cells, the researchers show that bisamide prototype drugs also block the invasive behaviour of cancer cells – probably through interacting with pirin.

If the binding to pirin is responsible, that could open up a potentially exciting new avenue for cancer treatment.

Study co-leader Professor Keith Jones, Professor of Synthetic Chemistry at the ICR, said: “It’s exciting to have discovered an inhibitor for this vitally important signalling network, which helps cancer cells to survive the strains and stresses of genetic mutations and continual growth and division. This research gives us a tool to understand how these stress signals work in cancer, and offers important clues for how that information can be turned into new treatments.”

Study co-leader Professor Paul Workman, Chief Executive of the ICR, said: “Our new probe will allow us to dissect out exactly what the effects are of blocking cancer’s stress signals, and could lead to the discovery of new forms of treatment – potentially quite quickly based on our powerful prototype drug.

"We’re particularly impressed by the strong effects we see in ovarian cancer cells that are resistant to standard platinum drugs, because drug resistant ovarian cancer is a very difficult condition to treat.

“This is a great example of a collaboration with multiple excellent partners which could lead to innovative drugs that work in a completely new way against cancer.”

'Encouraging new approach'

Dr Justine Alford, Cancer Research UK’s Senior Science Information Officer, said: “This encouraging new approach could help scientists find ways to target weaknesses in cancer cells. While it’s still early days, this approach could help develop new drugs that could be effective against many types of cancer and, by hitting one of cancer’s vulnerable spots, help reduce side-effects in patients.”

Rob James, Managing Partner at Sixth Element Capital LLP, said: “We are delighted that through the CRT Pioneer Fund’s investment in the HSF1 project we have been able to support the ICR’s important research in this area and to potentially pave the way for future new treatments to be taken into phase I clinical trials. If the first studies are successful we will seek industry partners to develop and commercialise drugs directed towards this signalling pathway.”


Paul Workman ovarian cancer Keith Jones
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