Starving cells may control melanoma

Wednesday 19 February 2014

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Could we treat melanoma by cutting off its food source?

The latest research from Sydney’s Centenary Institute and the University of Sydney suggests we could.

Last year the researchers showed they could starve prostate cancer. Now a further discovery opens up the prospect of a new class of drugs that could work across a range of cancers including melanoma.

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

Unlike normal cells, melanoma and other cancer cells rely on the amino acid glutamine instead of glucose for the energy required to divide and grow. Thus, in order to fuel their rapid growth, cancer cells need to pump glutamine into their cells.

New research published today in the International Journal of Cancer has found that not only do melanoma cells have more glutamine pumps on their surface, but that blocking these pumps stops their growth. The work was led by Dr Jeff Holst, who heads the Centenary Institute’s Origins of Cancer Research Group, together with post-doctoral fellow Dr Qian (Kevin) Wang.

Holst_2013.2 (credit Centenary Institute)

Jeff Holst in his lab at the Centenary Institute

“We’ve shown that if we starve melanoma of these essential nutrients, we can stop the cancer from growing,” says Dr Holst. “This involves blocking the protein pumps that move glutamine into tumour cells, which successfully slowed the growth of the tumours in cell cultures”, he says.

Although often curable if detected early, melanoma is one of the most difficult cancers to treat once it has spread, says Dr Holst, because it rapidly develops resistance to known therapies. “But a drug that specifically targets and inhibits the glutamine pump will give us a new and different approach from current treatments.”

“This work is leading a new wave with potential to develop cancer therapeutic agents. These drug targets, rather than mutations specific to the cancer, are exaggerated normal processes,” says Centenary Executive Director Mathew Vadas.

“This is a long journey to the clinic, but it’s an exciting development,” Dr Holst says. He hopes such a compound can be developed and tested in five to 10 years.

Last year Dr Holst’s group published a paper in the Journal of the National Cancer Institute showing that prostate cancer cells require another amino acid, leucine, for their growth. “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.”

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Background Information

Paper Abstract

Targeting glutamine transport to suppress melanoma cell growth

Amino acids, especially leucine and glutamine, are important for tumor cell growth, survival and metabolism. A range of different transporters deliver each specific amino acid into cells, some of which are increased in cancer. These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression. The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids. In this study, we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAFWT (C8161 and WM852) and BRAFV600E mutant (1205Lu and 451Lu) melanoma cell lines. While inhibition of LAT1 by BCH did not suppress melanoma cell growth, the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells, leading to inhibition of mTORC1 signaling. Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture. This included reduced expression of the cell cycle regulators CDK1 and UBE2C. The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown, which inhibited glutamine uptake, mTORC1 signaling and cell proliferation. Taken together, our study demonstrates that ASCT2-mediated glutamine transport is a potential therapeutic target for both BRAFWT and BRAFV600E melanoma.

About Jeff Holst

Head, Origins of Cancer Group, Centenary Institute

Dr Jeff Holst heads the Origins of Cancer laboratory in the Gene & Stem Cell Therapy Program at Centenary Institute as an Associate Faculty member. Jeff’s lab is focused on increasing our understanding of the metabolic requirements of tumours, which may lead to new treatments.

Jeff completed his PhD in 2003 at St Vincent’s Hospital Centre for Immunology in Sydney, before undertaking postdoctoral studies at St Jude Children’s Research Hospital in the USA. He returned to Australia in 2006, switching his focus from immunology to cancer research and received a Fellowship from the Cancer Institute NSW. He has received funding from the NHMRC, Cancer Council NSW, National Breast Cancer Foundation and the Prostate Cancer Foundation of Australia, the very charity he fundraises for during Movember.

About the Origins of Cancer research Group

Tumours require a constant supply of nutrients to maintain their growth advantage. Increased understanding of the nutrients required for tumours to grow and how they are brought into the cancer cells, may lead to new avenues to stop cancer growth.

Over the last decade, drugs designed to block blood vessel formation have provided an entirely new string to the cancer treatment bow. Blocking the blood supply restricts the amount of nutrients available to cancer cells. Since there are over 350 different nutrient transporters which can bring a variety of substrates such as amino acids into the cell, we propose that blocking specific transporters in cancer may offer new opportunities for therapeutic intervention.

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About the Centenary Institute

The Centenary Institute is an independent leader in medical research seeking improved treatments and cures for cancer, cardiovascular and infectious diseases. We are working to discover new prevention, early diagnosis and treatment options to enable each generation to live longer, healthier lives than the one before. Centenary’s affiliation with the RPA Hospital and the University of Sydney means that our discoveries can be quickly applied to the fight against disease in the clinic.

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