Author Interviews, Cancer Research, Personalized Medicine / 04.11.2015
Histone Biomarker May Guide Treatment of Pediatric Malignant Gliomas
MedicalResearch.com Interview with
Timothy Humphrey DPhil.
CRUK/MRC Oxford institute for Radiation Oncology
University of Oxford, UK
Medical Research: What is the background for this study? What are the main findings?
Response: Multiple mutations resulting in loss of a particular histone mark (H3K36me3) are frequently found in a number of cancer types. These include mutations resulting in loss of the tumour suppressor SETD2 (which trimethylates H3K36) and over-expression of the oncogene KDM4A (which demethylates H3K36me3), which together are observed in more than 10% of a number of cancer types. Notably, loss of H3K36me3 has been reported in more than 50% of pediatric high-grade gliomas. While loss of this histone mark is associated with poor prognosis, there is no targeted therapy yet.
Following observations made in fission yeast, we have found a new way to selectively target H3K36me3-deficient cancers using the WEE1 inhibitor, AZD1775. Surprisingly, treatment of H3K36me3-deficient cancer cells with the WEE1 inhibitor resulted in S-phase arrest. Further analysis revealed ribonucleotide reductase to be the target of this synthetic lethal interaction, thereby leading to dNTP starvation, replication fork collapse and cell death.
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