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Cancer drug resistance discovery

Posted: 19th June 2019

Researchers from SVI are part of an international team of collaborators that has made a discovery that may lead to more effective treatment and less side effects for a number of cancers including neuroblastoma, a cancer that occurs most commonly in infants and children under 5 years of age.

“Cisplatin was discovered in 1845 and licensed for medical use in 1978/79; it is a widely-used cancer drug that is quite successful against a wide range of cancer types ” said Professor Michael Parker, a National Health and Medical Research Council (NHMRC) Research Fellow. “However, many patients experience bad side effects, and most patients eventually develop a resistance to it, and we wanted to understand why.”

Cisplatin works by interfering with the process of DNA replication (the process by which a single double-stranded DNA molecule is copied to produce two identical DNA molecules), killing the fastest dividing cancer cells. It is from a family of platinum-based drugs, informally called platins. Almost 50 per cent of people receiving chemotherapy treatment are being treated with a platin drug.

What Professor Parker and joint first author Dr Lorien Parker, as well as the study collaborators from the Bio21 Institute, The University of Melbourne and researchers from Italy, Singapore and Switzerland identified, is an enzyme that inadvertently leads to cisplatin resistance.

“GST enzymes are found in every cell of the body; they are ‘good guys’ that protect us from toxic molecules which come from a variety of sources including the food we eat, smoking and exposure to UV radiation. The enzymes attack toxic molecules which are then pumped out of the cell and body.

“Using the process of X-ray crystallography, which is a technique used to determine the molecular structure of proteins, we were able to identify exactly where cisplatin was attaching itself to a specific GST enzyme, called GSTP1. But unlike GST’s normal activity, where it would pump the toxic cisplatin out of the cell, this attachment led to the GST acting like a sponge, soaking up and storing the cisplatin, rendering it ineffective and unable to do its job to prevent the proliferation of cancer cells.

“We are now looking at the design of new drugs that will prevent the GSTP1 enzymes from attaching to the cisplatin, so that this type of resistance is interrupted and cisplatin can continue to kill the cancer cells. Interestingly some of these GST inhibitors we are looking at are metal-based, like arsenic. Most people wouldn’t realise the role ‘precious metals’ play in cancer treatment, but they’ve been used in medicine for thousands of years.”

Jim Wilson's son Sam died of neuroblastoma when he was 6 years old; when he was told of this SVI discovery he said, “I know I speak for many when I say that a cancer diagnosis is devastating, but it is particularly hard for young children and their families to navigate.

Providing cancer patients with the tools to battle cancer – such as chemotherapy drugs – can provide both relief, and hope. If this research leads to a new drug that is able to reduce the bad side effects of cisplatin, and allow it to continue its work to destroy cancer cells, then in my eyes that’s a real game changer.”

The work was supported by an Australian Research Council (ARC) project grant with major equipment support from the Australian Cancer Research Foundation. Other support included a National Health and Medical Research Council of Australia (NHMRC) Dora Lush Scholarship and an International Centre for Diffraction Data Crystallography Scholarship; provided to Dr Lorien Parker, joint first author, who did her PhD at SVI.

Journal publication
The results of this study has been published under the heading "A structure-based mechanism of cisplatin resistance mediated by Glutathione Transferase P1-1," in the PNAS (Proceedings of the National Academy of Sciences of the United States of America).

About cisplatin
According to Wikipedia, cisplatin is used to treat a number of cancers.[1] These include testicular cancerovarian cancercervical cancerbreast cancerbladder cancerhead and neck canceresophageal cancerlung cancermesotheliomabrain tumors and neuroblastoma.[1] It is given by injection into a vein.[1]

Common side effects include bone marrow suppressionhearing problemskidney problems, and vomiting.[1][2] Other serious side effects include numbness, trouble walking, allergic reactionselectrolyte problems, and heart disease.[1] Use during pregnancy is known to harm the baby.[1] Resistance to the drug, even if only small, can be clinically important since administration of higher doses of cisplatin to counteract the problem can lead to severe multi-organ toxicities.

About neuroblastoma
According to the Neuroblastoma Australia website, neuroblastoma is the most common solid tumour of childhood. It is almost exclusively a childhood cancer occurring most commonly between the ages of 0-5 years.

It is a solid tumour arising from particular nerve cells which run in a chain-like fashion up the child’s abdomen and chest and into the skull following the line of the spinal cord. The most common site for the tumour to grow is in the abdomen. About 50% start in the adrenal gland above the kidney. Some tumours grow at the back of the chest and occasionally even higher up towards the neck.

Neuroblastoma is a rare disease with about 40 children diagnosed with neuroblastoma each year in Australia. There are no known reasons as to why this cancer occurs and there are no clear environmental links. There are rare cases where neuroblastoma runs in families due to a genetic mutation, but in most cases there is no known genetic cause.

Neuroblastoma is a very complex cancer and there are many different types that behave very differently. At one end of the spectrum are benign tumours that may even resolve spontaneously, while at the other end are aggressive tumours with an average survival rate of 40%. The cure rate for these “high-risk” tumours has only improved marginally in recent years but there is clear hope that this rate will change with some new drug discoveries coming through.

For more information please see: Structural biology