Molecular Arsonists: Degrading Oncogenic Transcription Factors to Reverse Tumor Immortality

Overview

Francisco Glioblastoma (GBM) is the most predominant malignant brain cancer in adults without prognosis improvement in decades. Nevertheless, 83% of GBM cases have Telomerase Reverse Transcriptase promoter (TERTp) mutations, enabling the GA-binding protein (GABP) transcription factor complex to bind and reactivate TERT expression, allowing the tumor to divide indefinitely. While directly targeting telomerase has systemic toxicity, targeting GABP may allow tumor - specific TERT silencing. Because targeting transcription factors with small -molecule inhibitors is nearly impossible, a novel approach is required. Last year, we designed a GABPB1 dominant negative, reducing TERT expression in glioma cells. Still, because the construct was large and remained intact, it could reactivate TERT. To improve our approach, we devised a strategy for creating biologic -based Proteolysis-Targeting Chimeras (bioPROTACs) to target the GABP. Using GABPA, the binding partner of GABPB1 and GABPB2, we engineered a GABPA dominant negative by mutating key DNA -binding residues to alanine. We then utilized AlphaFold3.0 to identify the smallest GABPA capable of binding to GABPB1/2 via in-silico modeling. Finally, we functionalized this minimal GABPA-DN by attaching a Ubiquitin degrader (SPOP) or a lysosomal degrader (CMA) domain. We observed an 80 -90% decrease in TERT expression and a near - complete degradation of all GABPB1 isoforms in tumor cells. Here, we present a strategy for the creation of biologic-based therapeutics targeting oncogenic transcription factors utilizing modern machine learning algorithms, validated using the master regulator of mutant TERT promoter- driven tumor immortality as a proof -of-concept, providing a powerful example for the potential applications it may have in other transcription factor-regulated diseases. California Southern The Power of Frequencies as a Treatment for Neurodegenerative Diseases: Which Sinusoidal Frequencies Impact Nematode Mutants Expressing ABeta1–42? Chloe Chen Brentwood School, Los Angeles, CA Alzheimer’s Disease and other related disorders have been increasing steadily as the population ages. The misfolding and accumulating proteins such as Amyloid -beta (Aβ) leads to neurodegeneration in these diseases. Available treatments are limited by invas iveness and side effects, raising the need to develop alternative therapies. The mutant strain smg-1 CL2355 contains a human Aβ transgene engineered into its pan -neuronal cells, causing impairments in cognitive function. This study observed the time for th e organisms (N2 Wildtypes and smg-1 hermaphrodites) to react in the form of backward sinusoidal locomotion, and the time for the organism to recover and return to the normal movement (forward-moving sinusoidal undulations), when exposed to the airborne frequency spectrum (2s; 100Hz, 450Hz, 1 -5kHz; 80dB SPL). The N2 reacted faster than the smg-1 across all frequencies except 4000Hz, to which the smg-1 reacted and recovered faster . Then, we investigated how the Aβ1 –42 protein in the smg-1 developed over multiple generations of exposure to 4000Hz for 30 minutes and used the Congo Red stain to target the Amyloid -beta protein in the smg-1 and N2 nine days after exposure. The buildup of Amyloid -beta1-42 plaques decreased in the smg -1 after each generation, calculated by comparing the mean gray value in the Amyloid -beta plaque of smg -1 and N2 over multiple generations of exposure to 4000Hz for 30 minutes. Identifying the effects of frequencies on the Aβ1–42 protein may have implications for treating dementia and potentially extending one’s sense of self and connections to loved ones.

Competition history

• JSHS 2025 Category not listed

Resources

• National JSHS abstract book ↗

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