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31-Jan-2019

International Research Team Led by Australian Scientists Discover a Potential Way to Treat and Prevent Cancer in Children with Neuroblastoma

SEATTLE, Jan. 30, 2019 /PRNewswire/ -- The MYCN oncogene has long been known to be a key cause of a number of deadly solid tumour cancers, including neuroblastoma, which claims more lives of children under the age of 5 than any other cancer.

Neuroblastoma is the most common solid tumour found in young children. In up to 25% of cases, the tumours contain an increased number of copies of MYCN, and children with these 'high-risk' neuroblastomas have a particularly poor prognosis.

To date, no drugs have been able to directly target MYCN, so scientists have looked at other ways to halt the progress of neuroblastoma.

One group of target molecules, known as polyamines, are known to be critical for cell growth and survival and are present in high concentrations in cancer cells. However, clinical trials of agents that target the polyamine pathway have proven disappointing.

In new research published this week in the international journal, Science Translational Medicine, a team jointly led by Professor Michelle Haber AM, Executive Director, and Professor Murray Norris AM, Deputy Director, Children's Cancer Institute, Australia, has uncovered a previously unknown and crucial link between polyamines and MYCN, revealing that the polyamine pathway is entirely regulated by the MYCN oncogene.

Discovering this link – by which MYCN controls polyamine levels in cancer cells, driving the growth and proliferation of the neuroblastoma cells – means that scientists for the first time have a potential therapeutic "way in" to disrupting cancer cell growth. 

Previously, the Children's Cancer Institute research team has shown that a drug called DFMO targets a gene involved in the synthesis of polyamines. There is currently a clinical trial underway at the Kids Cancer Centre, Sydney Children's Hospital, and in 14 leading US children's cancer centres, to study the use of DFMO when given with existing anti-cancer drugs, to treat children with relapsed neuroblastoma.

In the current study, researchers have identified the gene responsible for the uptake of polyamines by neuroblastoma cells and have shown that this gene can be inhibited using a drug called AMXT-1501.  By combining these two drugs, DFMO and AMXT-1501, with conventional chemotherapy, the research team was able to significantly increase survival in mice with established neuroblastoma tumours, as well as prevent tumour formation in mice who were tumour-free but genetically prone to developing the disease.

The newly discovered combination therapy is now being tested in the US in adult patients with a broad range of cancers, in Phase 1 clinical trials run by pharmaceutical company Aminex Therapeutics. The trial is listed on the NIH clinical trial registry at www.clinicaltrials.gov (Identifier NCT03536728).  

"This exciting new treatment approach warrants clinical investigation in children with MYCN-driven high-risk neuroblastoma, and potentially other cancers as well," said Haber. "While other treatment approaches in clinical evaluation are designed to inhibit polyamine synthesis, they do not impact polyamine uptake from the microenvironment. Our study suggests that both polyamine synthesis and polyamine uptake need to be inhibited for therapy to be effective."

Mark Burns PhD, President and Chief Scientific Officer at Aminex and an author on the paper, described the study's results as "impressive" and said they further bolster the company's excitement about the potential for polyamine depletion therapy as a new treatment approach. "These findings demonstrate the benefit of combining inhibition of polyamine synthesis with blockade of polyamine transport and suggest that combining AMXT 1501 and DFMO with standard chemotherapy may be a potent treatment strategy for high-risk neuroblastoma patients," he said.

Working with Aminex Therapeutics to lead the introduction of this new combination treatment for neuroblastoma into clinical trials is Associate Professor David Ziegler, paediatric oncologist at the Sydney Children's Hospital and a research Group Leader at the Children's Cancer Institute.

"These results are very exciting and offer a new and potent way to target childhood cancers," said Ziegler. "We have already shown in our current clinical trial that targeting polyamines with one drug (DFMO) can be safely achieved in combination with chemotherapy. By combining two drugs targeting the same pathway we have the potential to further improve the anti-cancer effect for these children. We are now working with Aminex to develop a children's formulation of AMXT1501 and once the initial adult trial is complete, we plan to open a clinical trial for children with the most aggressive cancers."

Joining Haber, Norris and Burns as a senior co-author on the study is Professor Giovanni Perini from the University of Bologna, Italy.

Foot note This collaborative study includes contributions from research institutions in a number of countries: Italy (University of Bologna), Germany (University of Cologne), USA (University of Pennsylvania, Harvard Medical School), and Australia (Children's Cancer Institute, Sydney Children's Hospital).

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 remains unchanged – to save the lives of all children with cancer and to eliminate their suffering. The Institute has grown to now employ nearly 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 minimize 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/ 

About Aminex Therapeutics

Aminex Therapeutics, Inc. is a clinical-stage biotechnology company focused on the development of a novel small molecule combination therapies for the treatment of cancer. Aminex has advanced AMXT 1501 + DFMO through target discovery, patenting, pre-clinical research and now into clinical development for the potential benefit of cancer patients. To date, the company has received backing of approximately $19 million from private investors. For more information, please visit www.aminextx.com 

About Kids Cancer Centre

The Kids Cancer Centre (KCC) at Sydney Children's Hospital, Randwick has been treating children with cancer and blood diseases in NSW, Australia and the Asia-Pacific region for nearly 50 years. Almost two thirds of children treated for cancer or leukaemia at the Centre are enrolled on clinical trials, in a unique model where research and clinical care are one, aimed at ensuring the best possible care for children and their families. During that time the survival rates for children with cancer have gone from 10 per cent to nearly 80 per cent. Clinical and research staff from the Centre have made major international and national contributions to the expansion of knowledge in the area: from important discoveries around bone marrow transplantation, chemotherapy for relapsed solid tumours and leukaemia, to the invention of novel anti-cancer drug combinations and minimal residual disease (MRD) testing in ALL. Centre staff have been leaders in devising new methods of outreach and home nursing, and in developing modern approaches to the bereaved family. These achievements have been founded on academic excellence and clinical expertise. In the past five years alone, Centre staff have published over 200 papers in peer-reviewed medical and scientific journals and have been awarded more than $60 million in competitive grant funding. Over the past 20 years a total of eight clinical staff have received Order of Australia honours for their work http://www.kids-cancer.org/

About Sydney Children's Hospital, Randwick

Each year, Sydney Children's Hospital, Randwick cares for more than 69,000 seriously ill and injured children from across NSW, Australia and beyond in a family-centred, multidisciplinary, expert environment. Sydney Children's Hospital, Randwick is one the country's leading centres in paediatric clinical and research excellence and is part of The Sydney Children's Hospitals Network (SCHN), the largest network of hospital and services for children in Australia.  For more information visit www.schn.health.nsw.gov.au

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Last Updated: 31-Jan-2019