Drugs developed to fight blood and other cancers could also help improve the efficiency of radiotherapy in the most commonly diagnosed low-grade brain tumour in adults, according to recent study findings.
Meningioma accounts for 36% of all primary brain tumours. While most are successfully treated by surgery, some that can’t easily be accessed need to be treated with radiotherapy. That can cause significant side effects and radiation damage to the brain, while resistance to radiotherapy can also result in tumour growth, reports News-Medical.net
The recent study at the Brain Tumour Research Centre of Excellence, University of Plymouth, scrutinised the effects of that radiation damage and ways of mitigating it. The results were published in The Lancet’s eBioMedicine journal.
Using meningioma cells, researchers discovered that radiation-induced damage can lead to cells producing an increased quantity of the enzyme Histone deacetylase 6 (HDAC6), which has previously been shown to contribute to tumour growth.
However, by administering the HDAC6 inhibitor Cay10603 prior to radiotherapy, they were able to inhibit cellular growth – and increase cell death – in meningioma samples.
The study was led by Dr Juri Na and Professor Oliver Hanemann, who say their findings represent a potential promising approach to improving the treatment outcomes of malignant meningioma.
The research also builds on extensive and ongoing work by the Centre of Excellence in Plymouth looking at the potential of already-approved medications to be repurposed as a way of helping brain tumour patients.
“This combination treatment will kill cancer cells more efficiently while avoiding serious side effects that could be caused by heavy radiation treatment, as we can administer a low dose of radiation along with Cay10603,” said research fellow Na.
Hanemann, director of the Brain Tumour Research Centre of Excellence at the University of Plymouth, added: “Pan-HDAC inhibitors have been approved by both the US Food and Drug Administration and the European Medicines Agency, but Cay10603 is not currently licensed in the UK. And no HDAC inhibitors like it have been utilised in clinical settings.
“It means there are still steps to overcome before this treatment can begin to benefit patients directly, but this is certainly a positive development when you consider the lack of existing treatments available to meningioma patients.”
Brain Tumour Research funds sustainable research at dedicated centres in the UK. It also campaigns for the government and larger cancer charities to invest more in research into brain tumours to speed up new treatments for patients and, ultimately, to find a cure.
Study details
Targeting histone deacetylase 6 (HDAC6) to enhance radiation therapy in meningiomas in a 2D and 3D in vitro study.
Juri Na, Shahana Shaji, C Oliver Hanemann.
Published in The Lancet eBioMedicine on 24 June 2024
Summary
Background
External radiation therapy (RT) is often a primary treatment for inoperable meningiomas in the absence of established chemotherapy. Histone deacetylase 6 (HDAC6) overexpression, commonly found in cancer, is acknowledged as a driver of cellular growth, and inhibiting HDACs holds promise in improving radiotherapeutic efficacy. Down-regulation of HDAC6 facilitates the degradation of β-catenin. This protein is a key element in the Wnt/β-catenin signalling pathway, contributing to the progression of meningiomas.
Methods
To elucidate the associations and therapeutic potential of HDAC6 inhibitors (HDAC6i) in conjunction with RT, we administered Cay10603, HDAC6i, to both immortalised and patient-derived meningioma cells prior to RT in this study.
Findings
Our findings reveal an increase in HDAC6 expression following exposure to RT, which is effectively mitigated with pre-treated Cay10603. The combination of Cay10603 with RT resulted in a synergistic augmentation of cytotoxic effects, as demonstrated through a range of functional assays conducted in both 2D as well as 3D settings; the latter containing syngeneic tumour microenvironment (TME). Radiation-induced DNA damage was augmented by pre-treatment with Cay10603, concomitant with the inhibition of β-catenin and mini-chromosome maintenance complex component 2 (MCM2) accumulation within the nucleus. This subsequently inhibited c-myc oncogene expression.
Interpretation
Our findings demonstrate the therapeutic potential of Cay10603 to improve the radio-sensitisation and provide rationale for combining HDAC6i with RT for the treatment of meningioma.
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