Using a combination of drugs and diet to block the many different ways tumours create energy and building blocks could offer potentially effective new cancer treatments, according to new research from the Francis Crick Institute.
Tumours are flexible in how they create the energy and the building blocks they need to survive and grow. If a treatment blocks one metabolic pathway the tumour can compensate by using another. In this study published in Nature Metabolism, Crick scientists have shown, in cells and mice, how using a combination of drugs to block multiple pathways could be more effective than the use of individual drugs.
Andrés Méndez-Lucas, lead author and former postdoctoral researcher in the Oncogenes and Tumour Metabolism Laboratory at the Crick, says: “How cancers create energy is like a flexible and complex maze. If you block one route, another arises to rescue the tumour cells”.
“Excitingly, our work in the lab has shown this flexibility can be overcome by using a combination of drugs to block various routes at the same time and so cut off the cancer’s back-up paths.”
Multiple paths to create energy
For example, when the team used a drug that blocks enzymes called glutaminases, they found tumours can instead use another group of similar enzymes, called amidotransferases, to create energy.
But when the researchers used a combination of drugs to block both sets of these enzymes in both mice and cell lines*, they showed it slowed down tumour growth more than the use of individual drugs.
“Understanding the flexibility of cancer metabolism is vital for the development of treatments that aim to block tumours from creating energy and building blocks. Our findings paint a really complicated network, where tumours can substitute certain enzymes and pathways for others,” says Mariia Yuneva, author and group leader of the Oncogenes and Tumour Metabolism Laboratory at the Crick.
How tumours require fat
The research team also uncovered that tumours treated with drugs designed to stop them creating certain metabolites can compensate for this by using metabolites that come from the diet.
For example, they treated mice with a drug blocking production of fat and placed them on either a high or low-fat diet. Their results showed that the drug was only able to slow down tumours on the low-fat diet.
Mariia further explains: “A metabolism-targeting treatment, when combined with an appropriate diet could one day make an impact on cancer growth. These early findings in mice will hopefully inform future clinical trials and help develop more effective treatment combinations.
“However, until clear results come out of controlled human trials, it’s important that patients should not change their diet and speak to their doctor if they have any concerns.”
The researchers plan to continue this work to find out more about the mechanisms tumours use in these different metabolic pathways and also to explore if there are any links between the types of metabolism used and a tumour’s genetics.
* The drug combination was tested in colorectal tumour tissue taken from two patients, human colon cancer cell cultures and in live mice. In all cases, the drug combination slowed down tumour growth more than the use of individual drugs.