New drugs aim to kill cancer cells by destabilising their DNA
Drugs that selectively destroy cancer cells by destabilising their DNA will be developed in a £6m project funded by the Wellcome Trust at the University of Sussex, in collaboration with AstraZeneca.
The initiative is part of a wider move by oncology researchers to discover ways to stop the normal evolution of tumours into more lethal forms that resist treatment.
The Sussex research aims at the biochemical network within cells that biologists call the DNA damage response — DDR — system.
The damage response system detects and repairs breaks in DNA that occur frequently because of environmental factors and chemical stress, as well as random errors as cells divide.
Cancer cells already have a somewhat degraded DNA damage response system, which enables them to mutate, proliferate and evolve rapidly.
The aim is to destabilise the process further so that cancer cells cannot repair the DNA damage — and the resulting genetic mayhem kills them.
Healthy cells can resist this partial destabilisation.
“Within four years we aim to have at least three new drugs in development, which exploit the defects in our DNA in order to kill cancer cells,” said Professor Simon Ward, head of Sussex’s Drug Discovery Centre. “They will be more effective treatments, very specifically targeted at genetic subsets of the population, which will involve less side-effects for patients.”
New DDR drugs could also increase the effectiveness of traditional chemotherapy and radiation treatment, which work by causing high levels of DNA damage, enabling oncologists to destroy tumours with smaller doses.
At present only one DDR drug is on the market: AstraZeneca’s Lynparza, which was approved for some genetic types of ovarian cancer in 2014 and is showing promising results in clinical trials against advanced prostate cancer.
Lynparza works by inhibiting the action of an enzyme called Parp that is involved in DNA repair.
AstraZeneca is developing a pipeline of compounds that will work across several different DDR biochemical pathways, on their own or in combination with other anticancer drugs. These involve blocking enzymes with names such as WEE1, ATR, ATM as Aurora B, as well as Parp.
Each product will be targeted at a specific genetic group of patients but estimates suggest that the DDR approach as a whole could treat as many as 40 per cent of cancers, said Susan Galbraith, head of AstraZeneca’s innovative medicines unit.
The company will contribute a range of technical, scientific and managerial support to the Sussex project. In exchange AstraZeneca will have first right to negotiate commercial development of any compounds that are discovered. “This sort of collaboration is extremely important for our cancer drug discovery programme,” said Dr Galbraith.