A new therapeutic target for childhood medulloblastoma
Chief Investigator: Professor Stuart Pitson
Funding Amount: $97,986
Recipient: University of South Australia
Medulloblastoma is the most common brain cancer in children. While the current treatment of surgery, radiotherapy and chemotherapy can increase survival rates for some children with medulloblastoma, this treatment often causes severe side effects and life-long disabilities. Thus, new therapies for medulloblastoma are desperately needed. We have identified a new therapeutic target for medulloblastoma, supported by compelling experimental data, and have developed new inhibitors of this target that offer promise for development as a medulloblastoma therapy. This proposal outlines the pre-clinical evaluation of this approach with successful outcomes likely to lead to future clinical trials for the treatment of medulloblastoma.
Researchers: Prof Stuart Pitson, A/Prof Quenten Schwarz, Dr Melinda Tea, Dr Briony Gliddon, Dr Jo Woodcock
Research Completed: 2022
Research Findings: Medulloblastoma, the most common brain cancer in children, is largely treatable, however current treatment is associated with lifelong side-effects. We have developed cutting-edge techniques to grow these cancer cells in the laboratory to more closely reflect patient tumours and have developed advanced pre-clinical models of medulloblastoma to assess new less toxic therapies, which to date have shown promising anti-cancer activity. In future, these findings may potentially lead to clinical trials and meaningful outcomes for children.
Brain cancer is the number one cause of cancer deaths for children aged 0-14. For medulloblastoma, the most common brain cancer in children, the current standard of care consists of surgery, radiotherapy and chemotherapy. Whilst this combination of therapies increases the survival rates for some children with medulloblastoma, it is often accompanied by severe side effects and life-long disabilities as a result. Thus, new therapies for medulloblastoma are desperately needed to provide an improved quality of life for these survivors.
Professor Stuart Pitson’s laboratory at the Centre of Cancer Biology has been taking a multifaceted approach to develop advanced pre-clinical models of medulloblastoma for testing new and existing less toxic anti-cancer treatments, following the identification of a new therapeutic target for medulloblastoma, and more specifically patients with a subtype of medulloblastoma known as sonic hedgehog (SHH) medulloblastoma. This subtype of medulloblastoma is relatively understudied due to both difficulties in growing cells from these tumours in a way that closely mimics the biology of the original patient tumour, and the scarcity of clinically relevant advanced preclinical models available worldwide.
With the support of the Channel 7 Children’s Research Foundation grant, we have developed cutting-edge approaches to grow human medulloblastoma cells in the laboratory by providing the correct signalling cues and microenvironment for growth, allowing us to maintain the cancerous properties of the original tumour, which are often lost over time. These approaches, combined with our drug screening program utilising a large panel of anti-cancer drugs has allowed us, for the first time internationally, to conduct drug screening for anti-cancer activity against SHH medulloblastoma tumour cells. This includes the evaluation of a new small molecule inhibitor we developed and patented that targets a key protein we identified to play an important role in SHH medulloblastoma formation and progression. These studies have identified drugs with highly promising anti-cancer activity against SHH medulloblastoma cells in the laboratory. The next step in this process is to test these drugs in clinically relevant advanced preclinical models of medulloblastoma.
Using our extensive expertise in brain cancer, and the support of the Channel 7 Children’s Research Foundation, we have generated a number of advanced preclinical SHH medulloblastoma models to evaluate the clinical potential of the drugs identified in our laboratory studies to have anti-cancer activity against SHH medulloblastoma. These models were not previously available in Adelaide, so this progress has us uniquely placed to commence testing our new therapeutic approaches for SHH medulloblastoma, which is currently underway. Furthermore, the local availability of these resources and preclinical models within Adelaide paves the way for further research and preclinical testing by our laboratory and in collaboration with other researchers locally, interstate and internationally. Whilst the prognosis and survival rates for children with brain cancer has markedly improved with time, there is still a desperate need to find new targeted therapies which minimise the adverse lifelong side effects associated with the existing therapies. Our progress to date has provided a pathway for the preclinical evaluation, prior to translation in clinical trials, of new targeted therapies with fewer toxic long term side effects. We hope that in time, these discoveries will lead to meaningful clinical outcomes for children and their families.
Future Outcomes: We have previously patented a novel set of small molecule agents targeting the 14-3-3 adaptor proteins for use as anti-cancer therapies. Work from this grant may, in the future, lead to expansion of the spectrum of cancer applicable to these inhibitors to forms of medulloblastoma.