Our primary aim is to develop new targeted therapies to improve the outcome for children with medulloblastomas. We seek to achieve this by investigating agents that target the apoptotic pathway in medulloblastoma cells. Our hypothesis is that by rationally combining pro-apoptotic agents with other treatment modalities, including other targeted therapies or standard-of-care cytotoxic therapies, it will be possible to overcome chemo- and radio-resistance, increase tumour treatment responses, decrease toxicities, and ultimately improve patient outcomes. Our aim is to evaluate these combinatorial strategies in vitro and in vivo and rapidly translate the most favorable therapeutic combinations to clinical trial.
New therapies for medulloblastomas are urgently needed. Medulloblastomas remain the most common malignant brain tumour of childhood, accounting for 20% of all primary paediatric CNS tumours. Whilst in recent years the survival rates for many patients have improved, the outcomes for infants and those with metastatic or high-risk tumours remains poor. Furthermore, current treatment regimens are highly toxic and often lead to devastating late effects. Targeting the apoptotic pathways in medulloblastomas offers a unique opportunity to develop novel therapeutic strategies that overcome tumour resistance, reduce the toxicity of conventional therapies and ultimately improve patient outcomes.
Apoptosis is the specific, ubiquitous mechanism by which cells undergo a programmed and highly regulated death. Activation of the apoptosis pathway is also a key mechanism by which cytotoxic drugs and radiation kill tumor cells. Overexpression of anti-apoptotic molecules in malignant cells has been shown to confer them with resistance to radiotherapy and chemotherapy and contribute to cancer progression.
In the second Specific Aim, we plan to investigate the potential synergy of the Inhibitor of Apoptosis Proteins (IAP) in conjunction with standard cytotoxic therapies. Our hypothesis is that overcoming the anti-apoptotic effect of IAPs may lead to the same synergistic effect as seen with targeted therapies, and thereby facilitate a reduction in the dose intensity and the subsequent morbidity and mortality incurred with current treatment modalities, particularly radiation therapy. Our laboratory expertise in apoptosis, and translational research, our successful studies with malignant gliomas, as well as our access to small molecule IAP inhibitors in late development, offer a unique opportunity to identify effective novel treatment strategies that can rapidly be translated to the clinic.