Influencing cancer drug development programmes
Collaboration between researchers and the pharmaceutical industry has led to major investment in cancer drug discovery programmes that target inhibitors in transporter proteins.
Professor Andrew Halestrap and his colleagues in the School of Biochemistry have pioneered research into proteins, known as monocarboxylate transporters (MCTs), that are found within the plasma membrane of cancer cells. Of the four proteins they have identified and characterised, one shows very high levels of expression in the most aggressive cancer cells.
Transporter proteins aid the movement of lactic acid out of the cell as it builds up following glycosis; the metabolic process of breaking down glucose to acquire energy. Most cancer cells have a particularly high rate of glycolysis. Rapidly growing tumour cells, for example, may have a glycolytic rate up to 20 times higher than neighbouring healthy cells.
A high rate of glycolysis results in the production of lactic acid, which the cancer cells must get rid of in order to survive. Transporter proteins facilitate the movement of lactic acid molecules across the membrane and out of the cell. Research revealed that inhibiting these proteins allowed lactic acid to build-up in the cancer cells, which eventually killed them.
Research collaborations pioneer anticancer treatments
Halestrap's research over the last 20 years has had a major impact on drug development programmes. Working directly with the leading biopharmaceutical company, AstraZeneca, their collaborations have revealed how a group of immunosuppressive agents act within the body. Their research is now exploring how these agents can be used in anti-cancer drugs.
AstraZeneca discovered that some agents they were developing for immunosuppressive therapies to prevent organ rejection were acting as MCT inhibitors. The University's research was instrumental in increasing AstraZeneca’s understanding of the pharmacology of these agents, in particular potent and novel MCT1 inhibitors. The modelled structure of MCT1 is being used to identify the binding site of other more specific inhibitors and in the design of novel inhibitors that may be used in chemotherapy. In conjunction with Cancer Research UK, clinical trials are currently under way to investigate a drug called AZD3965, which targets MCT1.
Halestrap's work, and other internal and external studies, has led to a new drug discovery programme directed towards identifying MCT4 specific inhibitors. AstraZenica has extended its collaboration with the University to better understand this form of anti-cancer treatment.
The extensive research carried out through the University has led the way for organisations to pioneer new forms of treatment against aggressive cancers. Pfizer Worldwide Research and Development is exploring MCT1 and MCT4 as therapeutic strategies against malignant tumours. The National Institutes of Health, the national medical research agency in the US, has awarded US$3.85 million to scientists from the Scripps Research Institute to investigate anti-cancer therapeutics that target MCT1 and MCT4.