Repurposing antihistamines to reduce treatment-related toxicity for children with WNT-medulloblastoma

Medulloblastoma is the most common primary brain cancer in children and can be divided into four sub-types based on clinical and genetic differences.

One subgroup, known as WNT-medulloblastoma, is the most widely researched and has an excellent prognosis, with overall survival reaching 90%. However, the post-treatment quality of life for WNT-medulloblastoma survivors is less encouraging, due to the barrage of chemotherapy, radiotherapy and surgical interventions these children have at such a young age.

This proposed work aims to specifically hijack the self-destruct mechanisms of cancer cells, whilst leaving healthy brain cells intact. Lysosomes are small sacs filled with enzymes and acid that recycle and remove waste inside cells. Studies have shown that the outer lining of cancer cell lysosomes are much more fragile than healthy cell lysosomes. This fragility allows us to use certain drugs to overload the lysosome, causing it to burst and release its acid into the cell, triggering natural cell death mechanisms.

A large number of clinically approved non-toxic drugs have this effect on cancer lysosomes, including many anti-histamines. We have preliminary data that demonstrates that loratadine (Clarityn), in combination with chemotherapy, reduces tumour size in a mouse model of glioblastoma, a highly aggressive adult brain tumour. We aim to confirm this effect in WNT-medulloblastoma cells and explore more fully how loratadine interacts with lysosomes in our model systems.

We will then compare standard-of-care treatment against treatment plus loratadine in our mice implanted with cells from WNT-medulloblastoma patients. We aim to show that through the addition of a non-toxic and cost-effective approved antihistamine, we can reduce doses of irradiation and/or chemotherapy to improve quality of life whilst maintaining the same level of therapeutic success currently seen in the clinic.