New drug approach puts the brakes on tumour growth

The size of breast and prostate tumours can be reduced significantly with a new approach that attacks them from different angles, according to a new study published in December in the British Journal of Cancer.

The approach combines a drug that stops cell division and causes cell suicide (STX140) with a molecule derived from sugar that starves cells of energy (2DG). The combination of the drug and the sugar-like molecule reduced the growth of tumours in mice by 76% in the research, carried out by a team at Imperial College London.

The scientists believe this new approach has the potential to tackle drug-resistant cancers and should have fewer toxic side-effects than current therapy.

Conventional chemotherapy and radiation therapy work by targeting the rapidly- dividing cells on the outside of a tumour. However, this leaves the slow-growing cells in the central part of the tumour to survive. By targeting both types of cell, the team found that they could reduce tumour growth significantly.

In the centre of a tumour where there is little or no oxygen, tumour cells are more reliant on a process called glycolysis to make energy from sugar molecules. The scientists were able to block glycolysis by modifying a glucose molecule so it could not be broken down. This molecule, called 2DG, starves tumour cells of energy and this makes them more susceptible to anti-tumour drugs, such as STX140.

STX140 targets the rapidly-dividing cells on the outside of a tumour. During cell division, cells build scaffolding made of tiny structures called microtubules to help transport DNA and other cell contents to each newly created cell. STX140 disrupts this miniature scaffolding, causing the cells to commit suicide, which in turn shrinks the tumour.

Dr Simon Newman, the corresponding author of the study from the Division of Medicine at Imperial College London said: “We are developing a completely new class of drug with STX140. The research is still in its early stages but we think that the combination approach has the potential to change cancer therapy in the future. We would now like to see STX140 go into clinical trials, initially as a monotherapy, and we hope we can achieve this within 18 months.”

The scientists believe the new approach may prevent tumours from becoming drug- resistant. The majority of tumours can over time become resistant to conventional chemotherapy that kills cells, so the treatment becomes less effective and the disease progresses. This is often because there is a long time between doses, during which drug-resistant cells have a chance to proliferate. However, the new combination therapy could be taken daily, so any drug-resistant cells would not have a chance to grow. Furthermore, the new combination therapy may have fewer toxic side-effects than current therapy as the dose of the cell-killing drug STX140 can be reduced significantly.

Professor Mike Reed, head of the Oncology Drug Discovery and Women’s Health Group from the Division of Medicine at Imperial College London said: “One great advantage of our new generation of cytotoxic drugs, such as STX140, is that they can be taken orally. At the moment, patients have to make frequent visits to hospital for their chemotherapy. Potentially our new approach would mean that patients could avoid this and just take tablets at home. This is an exciting new approach that we hope could improve patients’ quality of life.”

The team reached their conclusions after looking at 20 mice over 28 days. The mice were treated in four groups: the first group received a placebo, the second group was given 2DG alone, the third was given STX140 alone and the fourth received the combination therapy, 2DG and STX140.

In mice with breast cancer tumours, a daily oral dose of STX140 resulted in a 46% reduction of tumour volume compared to untreated tumours. It also reduced the number of blood vessels feeding the tumour. However, the combination of STX140 and 2DG reduced tumour volume in mice by 76% compared to untreated tumours. This combination therapy was just as successful in a mouse prostate tumour model.

STX140 was characterised and developed by Professor Mike Reed’s Oncology Drug Discovery and Women’s Health Group at Imperial College London. This research was funded by Sterix Ltd, a spin-out pharmaceutical company, founded by Professor Reed in collaboration with Professor Barry Potter at the University of Bath. Sterix is now part of the Ipsen group.

(Source: British Journal of Cancer: Imperial College London: January 2009)