| Project title | RNA Polymerase I inhibition as a novel therapeutic strategy for treating brain cancer |
|---|---|
Grant Amount | $345,000 |
Investigator Team | Early Career Fellow Dr. Andrew Garvie, Supervisor A/Prof. Lee Wong, Associate Investigator Prof. Ron Firestein. |
Grant Type | Early Career Fellowship |
Years | 2024-2027 |
High-grade paediatric glioblastomas are the most aggressive and common solid cancer in children, with a median survival of 1.5 years. A seminal discovery was the identification of recurrent H3.3 mutations in paediatric glioblastomas: H3.3K27M and H3.3G34R. These H3.3-mutated tumours frequently show concurrent mutations in ATRX and activation of the Alternative Lengthening of Telomeres (ALT) pathway to evade telomere loss and enable cell immortality. Based on the previous data from my host lab and new, unpublished data from my PhD study, I have compelling evidence that paediatric glioblastomas with histone H3.3 and ATRX mutations show severe ribosomal DNA (rDNA) repeat instability and, thus, are compromised in their ability to produce ribosomal RNA (rRNA) and, therefore, are hypersensitive to RNA Polymerase I (Pol I) inhibition. Our collaborator, Prof. Ross Hannan (ANU), has developed the “best-in-class” Pol I inhibitor PMR-116, which is able to cross the blood-brain barrier. I, therefore, propose to test PMR-116 efficacy on patient-derived glioma cell lines and organoid models. Outcomes from this study will confirm the potential use of PMR-116 as a new therapeutic approach for treating incurable brain cancers.
“This project aims to outline a rational treatment strategy for individuals diagnosed with brain cancer. The current first-line chemotherapy for glioma, temozolomide, indiscriminately targets fast-growing cells and increases the patient’s median survival to 1.5 years. Therefore, we must address this challenge by generating new therapeutics that increase patient quality of life and survival.”
Dr. Andrew Garvie
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