Dr. Norman Chiu (Chemistry & Biochemistry) received new funding from Massachusetts General Hospital for the project “Epitranscriptome Associated with Glioblastoma Therapeutic Resistance.”
More than half of the 18,000 patients diagnosed with malignant primary brain tumors in the U.S. each year have glioblastoma (GBM), the most common and most aggressive primary malignant brain tumor in adults. Over the last two decades, the major breakthrough in the treatment for GBM has been the addition of the DNA alkylating agent temozolomide (TMZ) to the standard of care (surgery and radiation) yielding an increase in the median survival from 12.1 months to 14.6 months. Despite this advancement, 90% of GBM patients die within 5 years, a colossal failure that has attributed to drug/TMZ resistance.
One of the major predictors of GBM response to TMZ is the intrinsic MGMT (O6-methylguanine methyl transferase) promoter methylation status, and patients whose tumors have transcriptional silencing of the MGMT gene (which occurs in approximately half of GBM tumors), are more likely to benefit from the addition of TMZ. Given that all glioblastomas recur to a tumor lesion with acquired resistance to TMZ, leading to patient death, studies are underway to unravel the molecular changes that occur during treatment and that characterize the therapeutically-resistant recurrence.
Among the other known mechanisms of drug resistance in cancer, the abnormalities in gene expression are likely to initiate the problem. At the cellular level, genes are transcribed into a variety of RNA molecules. In comparison to the adduction of genomic DNA, cellular RNAs are less protected and more prone to be modified by chemical or enzymatic reactions within the cell. Some RNA modifications are essential for normal cellular activities, such as folding of tRNA molecules, however, depending on the position of this adduct, the same RNA modification can have the opposite effect. Overall, the dynamic in epitranscriptome is expected to hold one of the keys to our health.
In this proposal, the researchers hypothesize that the epitranscriptome of GBM is altered when tumor cells develop TMZ resistance. RNA modifications have been associated to cancer, but were never studied in the context of therapeutic resistance. If specific RNA modifications are associated to TMZ resistance in GBM, these modifications as well as the specific modified RNAs can serve as novel biomarkers for prognosis or therapeutic resistance. Also, identification of associated RNA modifications can lead to novel therapeutic targets.