In recent years significant headway has been made to increase survival rates and decrease long-term complications for children with brain cancer and work being done in WA is helping to transform clinical practice globally.
Brain tumours are the major cause of childhood cancer deaths and the most common solid cancers of childhood affecting approximately 200 children in Australia annually. Survival statistics for childhood brain tumours (unchanged for over two decades) remain well below that of other childhood cancers, including leukaemia.
Improvement in childhood brain tumour treatment has been hampered by deficiencies in knowledge about the underlying biological causes. Over the past 10 years, advances in genomic technology and international collaboration means there is now the opportunity to personalise treatment by developing novel therapeutic approaches tailored to each molecular subtype of brain cancer. This can improve cure rates while minimising toxicities.
Medulloblastoma is the most common childhood malignant brain tumour. Current therapy consists of surgery, craniospinal irradiation (CSI) and multi-agent chemotherapy.
Only four drugs (which have been used for decades) are commonly used worldwide for upfront medulloblastoma treatment: cyclophosphamide, cisplatin, vincristine and lomustine. Despite improvements in survival, approximately 30% of children succumb to their disease. Those surviving are faced with lifelong side effects from their treatments including cognitive decline, developmental defects, endocrine abnormalities, and other cancers.
Brain Tumour Research Program
The Brain Tumour Research Laboratory at the Telethon Kids Institute was established in 2009. Our research harnesses the power of innovative model systems of childhood brain tumours, which we have developed to test the effectiveness of new treatments so that the most promising therapies can be taken through to the clinic.
The Brain Tumour Research Laboratory has developed a comprehensive and robust preclinical testing pipeline using sophisticated childhood brain cancer models and cutting-edge technologies. This is now one of the largest programs in Australia specifically focused on childhood brain tumours bringing together clinicians and scientists with a focus on providing laboratory evidence that will more accurately inform new paediatric brain cancer clinical trials.
A pre-clinical pipeline to discover new therapies
Many new cancer drugs exist that more precisely target the molecular abnormalities in cancer cells that drive tumour growth. For two major reasons, very few have improved clinical outcomes so far.
Firstly, these new drugs were not fully evaluated in model systems that accurately reflect the disease prior to clinical trial. Secondly, the drugs were not adequately assessed for their ability to penetrate the blood brain barrier (BBB) and effectively reach their target, the tumour.
We have now reached a tipping point in choosing the right drugs. There are more new drugs to assess through clinical trials than patients available.
We believe the answer to this conundrum is to increase the rigour of preclinical testing to identify and prioritise only the most effective drugs with the best chance of success for clinical translation. Our approach is to undertake this preclinical testing using sophisticated laboratory mouse models that we and our collaborators have developed.
These patient-derived xenograft models (PDXs) were created by taking brain cancer cells from children at the time of surgery and immediately implanting them into the equivalent location in the brains of mice. These PDX models closely mimic the clinical characteristics of childhood brain cancers and enable testing of many more drugs than could be evaluated in the clinic.
Ineffective drugs can be screened out, resulting in enrichment of the clinical trials pipeline for drugs that are BBB penetrant and truly active.
In designing our approach, we considered how to best incorporate new therapeutics in a clinical trial. Most new cancer drugs are tested in an early phase (I/II) clinical trial after patients fail all proven therapies. Outcome is dismal for patients at this disease stage because the tumours become highly treatment resistant.
Moreover, no new therapies have been established as frontline standard of care for decades. Consequently, the strategy to cure children with medulloblastoma is to identify drugs that enhance the efficacy of current treatments and identify compounds that have potential to be included in a frontline clinical trial.
From bench to bedside
Using this approach we discovered a novel drug, called LY2606368 or prexasertib that had never been used before in children with brain cancer. Chemotherapy used for medulloblastoma treatment works by breaking DNA strands. However, this triggers a repair response involving enzymes called cell cycle checkpoint kinases (CHK1/2). Consequently, cancer cells can repair this damage and keep on growing and dividing.
Prexasertib is a drug that stops CHK1/2 from inducing the DNA repair. When the cancer cells are treated with prexasertib at the same time as chemotherapy, they are no longer able to repair the DNA and the cells die. This significantly extended the survival of mice with medulloblastoma, and these findings have recently been published in Science Translational Medicine*.
This pre-clinical data led to the design, approval and NHMRC MRFF funding for an innovative international clinical trial called SJ-ELiOT (NCT04023669), carried out at Perth Children’s Hospital in partnership with St Jude Children’s Research Hospital (SJCRH) in the US. SJ-ELiOT is named in honour of four-year-old Perth boy Elliot Parish, who in 2011 lost a 15-month battle with medulloblastoma.
In this trial, patients with certain types of recurrent, progressive or refractory medulloblastoma are treated with one of two combination therapies involving prexasertib. This international trial will provide important safety and initial data to explore if this treatment option can slow or reduce the growth of the medulloblastoma. SJ-ELiOT demonstrates the effectiveness of our pipeline to successfully translate pre-clinical findings into the clinic.
Key messages
- Childhood brain cancer treatment has changed little in decades
- WA is at the forefront of new research
- A pre-clinical approach can determine which drugs have better prospects of improving outcomes.
ED: The author is co-head of the Brain Tumour Research Program at Telethon Kid’s Institute. He is funded by the Perth Children’s Hospital Foundation as the Stan Perron Chair in Oncology and Haematology.
– References available on request.
Author competing interests – nil