Blocking copper uptake in tumor cells may be clue to boosting immune system

August 18, 2020

Australian researchers have discovered that removing copper from the blood can destroy some of the deadliest cancers that are resistant to immunotherapy using models of the disease.

While immunotherapy, a treatment that works through a patient's immune system to kill the cancers, has proven to be a breakthrough for many cancer patients, offering real hope and for some even a cure - some cancers camouflage themselves from current immunotherapies by expressing the aptly titled Programmed Death Ligand or PD-L1.

Dr Orazio Vittorio and his team from Children's Cancer Institute in Sydney and UNSW Sydney published the findings today in the prestigious Cancer Research, a journal of the American Association for Cancer Research.

It is known that cancer cells such as brain cancer "feed" on copper, often having up to six times the normal levels of the metal inside the tumour cells. Dr Vittorio and colleagues, including Professor Maria Kavallaris AM, studied tumour samples from more than 90 patients with neuroblastoma and 90 patients with gliomas. Both these cancers have high mortality rates and to date have not responded well to cancer immunotherapy. Neuroblastoma accounts for 15% of total childhood cancer deaths and only 50% of patients with high-risk neuroblastoma patient survive their disease. Glioblastoma has the worst survival rate of all cancers, with only 5% of patients surviving 5 years past their diagnosis.

According to Dr Vittorio, these two cancers express PD-L1 as a way to hide from the immune system, explaining why these two cancers are so deadly.

By looking at the human biopsies the researchers found a correlation between high levels of copper and increased expression of PD-L1. The researchers then showed for the first time that copper levels could control the expression of PD-L1 in cancer cells.

The researchers went on to use an analogue of a drug, called TETA, that is currently used in the treatment of Wilson's Disease, which is a rare genetic disorder characterized by excess copper stored in various body tissues. They used this drug in animal models of neuroblastoma and glioblastoma to reduce the amount to copper in the tumour cells, leading to a reduction in the expression of PD-L1.

"When these mice were given immunotherapy there was a significant reduction in the size of their tumours," Dr Vittorio said.

"Given that TETA is already in use in a number of clinical conditions and it is inexpensive and easy to manufacture, this may offer a viable treatment alternative for those cancers that are resistant to current immunotherapies."

Neuroblastoma claims more lives of children younger than five than any other cancer. Children like Luciano who was diagnosed at 14 months, endured three operations and eight rounds of chemotherapy. ''We are lucky because he responded well to treatment, but there were so many kids who have been lost. This research will help give hope to more families and children in the future'' his mother Maria said.
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This collaborative study includes : Children's Cancer Institute, UNSW Sydney, Peter MacCallum Cancer Centre, University of Bologna.

This work was supported by grants from Tour de Cure, Ross Trust foundation and Cure Cancer Australia.

About Children's Cancer Institute

Originally founded by two fathers of children with cancer in 1976, Children's Cancer Institute is the only independent medical research institute in Australia wholly dedicated to research into the causes, prevention and cure of childhood cancer. Forty years on, our vision is to save the lives of all children with cancer and improve their long-term health, through research. The Institute has grown to now employ over 300 researchers, operational staff and students, and has established a national and international reputation for scientific excellence. Our focus is on translational research, and we have an integrated team of laboratory researchers and clinician scientists who work together in partnership to discover new treatments which can be progressed from the lab bench to the beds of children on wards in our hospitals as quickly as possible. These new treatments are specifically targeting childhood cancers, so we can develop safer and more effective drugs and drug combinations that will minimise side-effects and ultimately give children with cancer the best chance of a cure with the highest possible quality of life. More at http://www.ccia.org.au

Children's Cancer Institute Australia

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