Glioblastoma multiform (GBM) is the most aggressive and prevalent form of brain cancer, with average survival expected to be less than two years from diagnosis. GBM affects the glial cells of the central nervous system causing damage to regular brain function including memory, hearing, and vision. Current therapeutics are associated with dangerous complications, such as irreversible neurological deterioration, and have limitations due to GBM drug resistance. GBM has virtually no long-term survival even with treatment, requiring novel therapeutic strategies. Development of a deeper molecular understanding can help identify new targets for elucidation of this disease. Computational methods can help alleviate this dilemma by using available GBM and healthy genomes to identify new potential targets responsible in disease development. This work utilizes experimental and bioinformatics analysis, identifying a potential prognostic marker of GBM within the olfactory receptor 2T7 (OR2T7) gene, displaying the mutation, D125V. OR2T7 is a G-Protein Coupled Receptor (GPCR), but its function is uncharacterized and underexplored. The OR2T7 D125V mutation occurs in 13% of GMB samples from the cancer genome atlas (TCGA), but not in any general population samples. Disease survival rate analysis illustrates that patients with the D125V mutation have an average of three months shorter survival than those without this mutation. Experimental results suggest OR2T7 D125V downregulates RhoB, a key marker in cell proliferation. Homology modeling and molecular dynamics (MD) simulations have provided preliminary structural insight and dominant morphologies on loop-movement of membrane-embedded, cytofacial-facing D125V, demonstrating a possible obstruction of G-Protein binding on the cytofacial exposed region. This work identifies a new, unexplored potential target in GBM via bioinformatics analysis, while also determining preliminary mechanistic pathways and structural morphologies of OR2T7 using both experimental and computational methodologies. Collectively, this work suggests that OR2T7 D125V rescues GBM cells from apoptotic pathways, indicating it as a novel tumor-suppressor gene and a viable candidate for drug discovery.

Molecular insights into OR2T7: Coupled computational and experimental techniques reveal a novel prognostic marker of glioblastoma multiform

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.