Research And Grants

Targeting RRNA Modification and SNORNA Function, A Novel Concept to Treat Aggressive Medulloblastoma

     Medulloblastoma (MB) is the most common malignant brain tumor in children. Treatment has improved survival in recent years, but patients are frequently left with devastating neurocognitive sequelae. Patients in molecular subgroups 3 and 4 still experience a high mortality rate. Our lab focuses on RNA-mediated processes to identify new pathways contributing to MB development. Our ultimate goal is to identify more effective and less aggressive therapeutic strategies. 

     Ribosome biogenesis, the generation of mature ribosomes, has been established as a cancer vulnerability, with cancer cells demanding increased and specialized protein production. Understanding the differences in ribosome biogenesis between normal and cancer cells and the contribution of its different components (RNA and protein) to tumor development is critical to advancing the use of ribosome biogenesis inhibitors in the clinic. This knowledge is particularly relevant in the case of highly aggressive tumors such as Groups 3 and 4 MBs. 

     Ribosomal RNA (rRNA) is a critical component of the ribosome. Chemical modifications in rRNA are required for the assembly of the ribosome. snoRNAs, a particular type of non-coding RNA, regulate rRNA modification by guiding modifying enzymes to specific positions in rRNA via base pairing. The pattern of rRNA modification can alter ribosome composition and influence protein production. We propose that in cancer cells, snoRNAs create a distinct pattern of rRNA modification that influences the assembly and selection of ribosomal protein, “shaping” the ribosome to enhance the expression of factors contributing to oncogenic phenotypes.

     A particular protein modification called PARylation is essential for assembling complexes implicated in ribosome biogenesis. Poly (ADP-ribose) polymerases (PARPs) add this modification to target substrates (proteins). PARP inhibitors have started to be explored to treat pediatric malignancies, including MB. Based on the connection between PARylation and ribosome biogenesis, we propose to evaluate if combinations of PARP and ribosome biogenesis inhibitors can be more effective than PARP inhibitors alone in treating MB.

Innovation and Impact. Our research is novel since the contribution of ribosome biogenesis to medulloblastoma development has not been systematically investigated.  This study will reveal how rRNA modification and snoRNA function “shape the ribosome” to enhance translation in Groups 3 and 4 medulloblastomas. Second, we will evaluate the concept of combining PARP and ribosome biogenesis inhibitors as a treatment option for medulloblastoma. 

Specific Aim 1) snoRNAs and rRNA modifications as contributors to medulloblastoma development

Hypothesis. We propose that a specific snoRNA signature “shapes the ribosome,” favoring the translation of genes in pathways critical for MB growth. 

1A. We will use genomic approaches to characterize snoRNA expression in MB Groups 3-4 cell lines, tumors, neuronal cells, and cerebellum and identify differentially expressed snoRNAs. 

1B. Considering the results of 1A, we will select 10 snoRNAs differentially expressed in medulloblastoma to evaluate their contribution to cancer phenotypes and treatment response. The top hits will be evaluated for their impact on gene expression. 

Specific Aim 2. Testing combined PARP and ribosome biogenesis inhibition as a treatment strategy 

Hypothesis. PARP inhibition arises as a treatment option for pediatric tumors. Genomic screenings determined that multiple genes regulating ribosome biogenesis confer sensitivity to PARP inhibitors. The result could be explained by the fact that protein associations in complexes regulating ribosome biogenesis depend on poly-ADP-ribosylation (PARylation). Therefore, we propose that combinations of PARP and ribosome biogenesis inhibitors could be more effective than PARP inhibition alone as a cancer treatment. 

2A. We will evaluate whether PARP inhibition affects snoRNA function and the modification of rRNA in MB cells. 

2B. Building on ribosome biogenesis dependence on PARylation, we will conduct a screening in MB Groups 3-4 cells to evaluate two combination strategies: 1) PARP + ribosome biogenesis inhibitors and 2) PARP inhibitors + modulation of snoRNAs identified in Aim 1.