Dr. Luiz Penalva of UT Health Science Center and Dr. Andrew Beekman of the University of East Anglia presented groundbreaking research focused on ribosomal RNA (rRNA) modification and its role in the progression of medulloblastoma, one of the most aggressive pediatric brain tumors. Their collaborative work explores how targeting fundamental cellular mechanisms may open new therapeutic avenues.
Ribosome Biogenesis and Medulloblastoma
Dr. Penalva explained that cancer cells, including medulloblastoma, require accelerated and specialized protein production to sustain their rapid growth. This process depends heavily on the ribosome, the cellular machinery responsible for protein synthesis. Unlike normal cells, cancer cells often re-engineer ribosomes to enhance efficiency and favor the translation of oncogenic pathways.
A critical step in this process is ribosomal RNA modification, guided by small nucleolar RNAs (snoRNAs). These modifications influence how ribosomes select and translate messenger RNAs, ultimately shaping the cancer cell’s behavior. Dr. Penalva’s team developed a sequencing platform to characterize snoRNAs in medulloblastoma. Their studies revealed unique patterns of snoRNA activity, particularly in the aggressive Group 3 and Group 4 subtypes, suggesting that these molecules may be drivers of tumor growth.
Targeting DKC1: A Novel Approach
The team identified DKC1, an enzyme central to rRNA modification and regulated by the oncogene MYC, as a promising therapeutic target. Increased levels of DKC1 in medulloblastoma appear to alter ribosome formation, fueling cancer progression.
To address this, Dr. Penalva’s group partnered with Dr. Beekman, a medicinal chemist specializing in cancer-related protein interactions. Dr. Beekman’s team developed peptide inhibitors designed to disrupt DKC1 activity. Inspired by naturally occurring mutations that reduce ribosome function in rare genetic disorders, they engineered synthetic peptides capable of interfering with DKC1’s protein-protein interactions.
Laboratory studies showed that these inhibitors effectively reduced the viability and proliferation of medulloblastoma cells without harming normal brain cells. Importantly, the treatment also lowered levels of cancer-associated snoRNAs and disrupted additional processes, such as telomerase activity, further weakening the tumor’s survival mechanisms.
Toward New Therapies
The next stage of this work involves optimizing these peptide inhibitors for therapeutic use. One key challenge is ensuring that the compounds can cross the blood-brain barrier to reach tumors effectively. Strategies under development include chemical modifications and small molecule alternatives that may provide more clinically viable solutions.
Beyond medulloblastoma, the researchers emphasized that rRNA modification and snoRNA activity are altered in multiple cancer types, suggesting that these therapeutic strategies could have broader applications in pediatric and adult tumors.
Looking Ahead
Together, Dr. Penalva and Dr. Beekman’s research underscores the potential of targeting ribosome biogenesis as a novel cancer treatment strategy. By combining cutting-edge molecular biology with medicinal chemistry, their work is laying the foundation for therapies that could one day offer new hope for children battling medulloblastoma.