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Investigational drug found to boost treatment efficacy in paediatric brain cancer

pharmafile | July 12, 2017 | News story | Research and Development | AT/RT, Cancer, DIPG, TAK228, biotech, drugs, pharma, pharmaceutical

Researchers from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, US, have revealed in a report that the drug TAK228 could be used to boost treatment in two deadly forms of paediatric cancer: Diffuse Intrinsic Pontine Glioma (DIFG) – an aggressive cancer of the brainstem which occurs in around 3,000 children worldwide, almost always resulting in death even with treatment – and Atypical Teratoid/Rhaboid Tumours (AR/RT), the most common cancer in infants, with average survival times of less than 12 months.

TAK228, or MLN0128 as it is also known, has been documented on its ability to traverse the blood-brain barrier and inhibit production of mTOR, a protein which fuels cancer when it merges with other proteins, enabling the disease to grow, spread and become resistant to treatment attempts.

Both AT/RT and DIPG are associated with increased mTOR activity, and based on this knowledge, the team, led by Eric H Raabe, Assistant Professor of Oncology and Instructor of Pathology, theorised that TAK228 could be used as a potential treatment for the diseases. They discovered that, when combined with radiation in the treatment of DIPG, the drug led to the death of almost twice as many cancer cells than radiation alone – Raabe and his team believe this points to TAK228 sensitising the cells to the effects of radiation.

On AT/RT cells, the drug produced a similar effect, and when combined with chemotherapy cisplatin and applied to human AT/RT tumours in mice, the animals lived 30 days longer than with either treatment alone – no mouse receiving singular treatment survived longer than 25 days, while 40% of those receiving combination therapies lived more than 60 days.

“Both of these papers set the stage for clinical trials for TAK228,” explained Dr Raabe. “Our experiments show that TAK228 can make traditional chemotherapy and radiation more effective, which may offer hope to patients for whom current therapy doesn’t work very well.”

The team is now pursuing the relationship between TAK228 and radiation, and whether this combination effect can be heightened, as well as future treatment applications.

Matt Fellows