Gliomas account for about 60% of all primary central nervous system tumors. Glioblastoma (GBM or grade IV glioma), which comprises 51.2% of all gliomas, is the most malignant form. 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. Nevertheless, 90% of patients receiving both TMZ and radiation die after 5 years, a colossal failure that has partially attributed to drug resistance. At the cellular level, ribonucleic acid (RNA) plays a central role in many cellular processes and serves as structural components. In comparison to the modification of genomic DNA, cellular RNAs are less protected and more prone to be modified by chemical or enzymatic reactions within the cell. Up to date, there are 74 known RNA modifications in eukaryotic cells. Some RNA modifications are essential for normal cellular activities, such as folding of tRNA molecules, however, depending on their positions, the same RNA modification can have the opposite effect. The epitranscriptome is further complicated by the concurrent activities of writers and erasers of RNA modifications. Overall, the dynamic in epitranscriptome is expected to hold one of the keys to our health. We hypothesize that the variations in GBM epitranscriptome plays an important role in TMZ resistance. Using accurate mass spectrometric method to detect RNA modifications, we aim to validate the association of specific epitranscriptomic profile with TMZ resistance in GBM using both in vitro and in vivo patient-xenograft models. Further, we will use different experimental approaches to study the role of epitranscriptome in the development of TMZ resistance in GBM. Finally, we will attempt to unravel the target associated with TMZ-resistance specific mRNA modification and will evaluate them as a potential target for GBM adjuvant therapy in combination with TMZ. Overall, we expect to categorize the role of RNA modifications associated with TMZ resistance, thus further enhance our understanding on the role of epitranscriptome in the development of chemotherapeutic resistance in GBM.
Therapeutic resistance is one of the main reasons for relative low survival rate of glioblastoma (GBM) patients. In the first part of this proposed study, we aim to confirm our initial results on the association of specific epitranscriptomic profile to GBM therapeutic resistance. In the second part of this proposed study, we will use different experimental approaches to study the role of epitranscriptome in the development of GBM therapeutic resistance.
