Children's brain cancer drug breakthrough
Around 400 children in the UK develop brain tumours each year with boys affected slightly more often than girls.
Medulloblastomas are the most common type of malignant tumour developing in the cerebellum.
The tumours are most commonly diagnosed at around five years old and treatments can include surgery, radiotherapy and chemotherapy.
While treatments are improving, success rates still lag behind other childhood cancers, particularly with an aggressive form of the cancer.
Only two fifths will survive the most aggressive form compared to over four fifths in less severe forms.
US researchers identified a new combination therapy for the most aggressive form of medulloblastoma, a fast growing type of paediatric brain cancer.
In lab tests the drugs kill cancer cells without being toxic to normal cells and researchers hope to start clinical trials.
Adjunct professor Robert Wechsler-Reya at Sanford Burnham Prebys Medical Discovery Institute said: “Our goal was to identify drugs with minimal toxicity that we can move quickly from the laboratory to the clinic, where new therapeutic options are desperately needed.
“Using high-throughput drug screening, we identified a compound that cooperates with a second drug to inhibit tumour growth in vitro and in vivo.
“In general, clinical trials for medulloblastoma are challenging because of the limited number of patients.
“Moreover, given the variability of the disease, most therapies will only work on a subset of patients.
“Figuring out which patients will respond to which therapies is a major goal of research in the field.
“If we can tailor therapies based on the genetic make up of the tumour - a strategy commonly referred to as personalised medicine - this could have an enormous impact on patients with this disease.”
Of the four distinct forms of medulloblastoma, patients with Group 3 tumours have the worst prognosis - only 40 per cent become long-term survivors compared to 80 per cent of other medulloblastoma patients.
Most Group 3 medulloblastoma cancers have high levels of the MYC oncogene, which causes cells to divide uncontrollably and form tumours.
Using mice with Group 3 medulloblastoma tumours, the study demonstrated that the combination of two drugs, histone deacetylase inhibitors (HDACIs) and phosphatidylinositol 3-kinase inhibitors (PI3KIs), potently kill mouse and human medulloblastoma cells with minimal toxicity to normal cells.
Assistant professor Yanxin Pei at Children’s National Medical Center in Washington said: “Our initial screen identified several HDACIs that killed MYC-activated medulloblastoma cells without harming normal cells.”
“The most potent of these compounds, panobinostat, is in clinical trials for other cancers but has not been tested for medulloblastoma.”
Postdoctoral fellow Dr Kun-Wei at Sanford added: “Additional studies revealed that panobinostat works by promoting the activity of FOXO1, a gene that interferes with the MYC oncogene.
“We figured that panobinostat and a PI3KI - also known to activate FOXO1 - might synergise to block cancer cell survival.
“Indeed, the combination therapy significantly improved survival of mice with human MYC tumours compared to each drug on its own.”
The study was published in Cancer Cell.