The Three Rs Of Cancer Survival
Solid tumours such as brain tumours are highly resistant to chemotherapyterm and radiation. One reason for this is a ‘reduce, reuse, recycle’ strategy that these tumours use to survive treatment. By developing a cancer drug that targets this recycling pathway, Malaghan Institute of Medical Research scientists have struck upon a novel approach for combating otherwise resistant and aggressive cancers.
As part of a collaborative cancer drug discovery programme with Prof Rob Smith from the Department of Chemistry at Otago University, and Dr Lesley Larsen from the New Zealand Institute for Plant and Food Research Ltd, senior Malaghan Institute scientists Prof Mike Berridge and Dr Melanie McConnell developed and tested a series of novel anti-cancer drugs.
One of these compounds, PMT7, was chosen as a candidate for further study based on its ability to kill certain types of previously drug-resistant cancer cells.
“Tumours grow and survive in relatively hostile environments within the body,” said Dr McConnell. “They are under attack from the body’s defences and have only limited availability of oxygen and nutrients to sustain their rapid growth.”
It is now understood that cancer cells rely heavily on an energy-production pathway called glycolysis to meet their energy needs when oxygen levels are low, while different recycling and salvage mechanisms such as autophagy are used to survive starvation.
“Autophagy is a form of cellular recycling where a cell starts breaking itself down and reusing its components to sustain its growth,” said Dr McConnell. “It is often induced in response to chemotherapy, where it aids cancer cell survival.”
“We discovered that one of the ways PMT7 works is by blocking autophagy - in doing so it kills the highly resistant glycolytic cancer cells that rely on this pathway in order to survive,” she says.
Their work, which has just been published in the international scientific Journal of Cellular Biochemistry, suggests that PMT7 and its derivatives could be used to eradicate populations of cancer cells that are resistant to traditional therapies.
“Killing cancer cells by directly blocking glycolysis has been studied for decades but also leads to the death of normal cells that depend on glycolysis for energy production, such as rapidly growing T cells,” says Dr McConnell. “Our research suggests that a more effective scenario would be to target the cancer cells vulnerable spot – its need to undergo recycling to prevent starvation under conditions of stress.”
This approach could potentially leave normal cells unharmed, thus reducing the likelihood of unwanted side-effects, because healthy cells growing in a nutrient and oxygen rich environment do not need to use these recycling mechanisms.
“By developing a drug that specifically targets the cancer cells that survive chemotherapy treatment, we have a greater chance of completely eradicating a patient’s cancer,” says Dr McConnell. “While PMT7 is not the ideal drug, with relatively high concentrations needed for maximum efficiency, it provides a promising lead compound to derive new drugs from.”
Developing cancer drugs that complement existing chemotherapies by also blocking the cancer cells ability to recycle is a promising new area of drug discovery that warrants further investigation.
The Malaghan Institute would like to acknowledge the Genesis Oncology Trust, the Cancer Society of New Zealand and Sir Roy McKenzie for supporting this research.