Scientists at the Auckland Cancer Society Research Centre (ACSRC) and Maurice Wilkins Centre for Molecular Biodiscovery and partly supported by AICR have designed a new compound that starves certain cancer cells of glucose, depriving them of energy.
The potential of the compound, STF-31, as an anti-cancer drug has been demonstrated in the laboratory through a collaboration with researchers from the Stanford University School of Medicine, and the findings have been published today in Science Translational Medicine.
“Standard cancer therapies attack healthy tissue as well as cancer cells, causing side effects that can limit treatment,” explains Associate Professor Michael Hay from the ACSRC at The University of Auckland and the Maurice Wilkins Centre. “By designing new drugs that target some of the abnormal biological processes unique to cancer cells, it may be possible to fight cancer with minimal side effects.”
Dr Lara Bennett from AICR said “this is a great example of how this targeted approach of designing chemicals can help in the development of new and better cancer treatments.’
One of the abnormal features of many cancer cell types is a change in the metabolic processes that turn glucose into energy. “Normal cells can use glucose efficiently, whereas many cancers produce energy inefficiently through aerobic glycolysis. These cells become addicted to glucose and need to import large quantities of glucose to survive,” explains Dr Hay.
“Using STF-31 we have shown that it is possible to selectively inhibit the ability of certain cancer cells to take up glucose. This starves them of energy and causes them to die. Importantly, treatment with STF-31 did not appear to cause toxicity in normal cells and so presages a novel way to selectively target cancer cells.”
The research focused on renal cell carcinoma, the most common form of kidney cancer in adults. The disease is resistant to standard chemotherapy and often requires surgical removal of the affected kidney. Most renal cell carcinomas possess a specific mutation that makes them highly dependent on glucose.
High-throughput screening of large libraries of small molecules at Stanford University identified a simple compound capable of selectively killing renal cell carcinoma. Based on this lead, medicinal chemists at the ACSRC in New Zealand created a series of drugs, including STF-31, for testing in the laboratory and showed that they acted by inhibiting a protein that transports glucose into cells. A series of biological experiments at Stanford University showed that STF-31 almost halved the amount of glucose taken up by renal cell carcinoma tumours in mice, and significantly slowed tumour growth.
“Renal cell carcinoma is one example of a cancer that becomes dependent on glycolysis, but many other tumour types avidly take up glucose, and this is used for PET scanning to identify and monitor these tumours. So this therapeutic approach has the potential to treat and monitor activity in a broad range of cancers.”
The work initially arose from a collaborative research programme led by Professor Amato Giaccia at Stanford University and Professor Bill Denny, Co-Director of the ACSRC and a Maurice Wilkins Centre principal investigator, and funded by the United States National Cancer Institute.
It has been continued in New Zealand by Associate Professor Hay and Drs Muriel Bonnet and Jack Flanagan with support from the Maurice Wilkins Centre and the Association for International Cancer Research (AICR). Based on the work, STF-31 has been licensed for preclinical testing to Ruga Inc, a Palo Alto-based biotechnology company.