Potential new approach to treating melanoma

Source: Life Scientist, February 2014

Recent research has found that blocking the transporters that deliver amino acids like glutamine into melanoma cells slows the rate of cell growth in culture.

The work, led by Dr Jeff Holst, who heads the Centenary Institute’s Origins of Cancer Research Group, together with postdoctoral fellow Dr Qian (Kevin) Wang, provides a potential new tack to treating metastatic melanoma.

Australia has the highest rate of melanoma in the world. Melanoma is the deadliest form of skin cancer and the third most common cancer in Australia.

Melanoma is often curable if detected early, but it is one of the most difficult cancers to treat once it has spread because it rapidly develops resistance. Combination treatments thus provide the best prospect for a cure.

Unlike normal cells, melanoma and other cancer cells rely on amino acids, in particular leucine and glutamine, to provide the energy for their growth, survival and metabolism.

A range of different transporters delivers each specific amino acid into cells, and the expression of some of these transporters is increased in cancer cells.

About half of melanoma patients have BRAF mutations in their tumours and current therapy focuses on inhibiting a particular signalling pathway (MAPK), which is involved with the most common BRAFV600E mutation.

The researchers investigated melanoma cell lines with different genetic backgrounds – C8161 cells, which are BRAF wild type but harbour a mutation in the p53 gene, and 1205Lu cells, which contain the BRAFV600E mutation and exhibit activated PI3-kinase signalling.

They found that the melanoma cells lines had more of the leucine transporter, LAT1/4F2hc, and the glutamine transporter, ASCT2, on their surface compared to normal cells and that these transporters were expressed on both BRAF wild type and BRAFV600E mutant cells.

They then showed that blocking the ASCT2 transporter decreased glutamine and leucine transport into the melanoma cells, which, in turn, inhibited growth.

“We’ve shown that if we starve melanoma of these essential nutrients, we can stop the cancer from growing,” said Dr Holst.

“We first demonstrated this nutrient pumping mechanism in prostate cancers, and it now looks like it occurs in a broad range of cancers, particularly solid cancers such as melanoma. This opens the possibility of designing therapies that can be used to block nutrient pumps across multiple cancers.”

This approach of inhibiting the glutamine pump provides a different way to combat melanomathan current treatments.

Dr Holst admitted it is a long way to the clinic but hopes such a compound can be developed and tested in five to 10 years.