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Updated: Sep 13, 2025
Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
SVC112: From Hummingbirds to Head and Neck Cancer
Tin Tin Su1,2
1Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA. tin.su@colorado.edu.
Abstract:
Many organs in a Drosophila melanogaster larva have a remarkable ability to regenerate. Studies of these have facilitated genetic and cell biological analyses that uncovered the role of evolutionarily conserved signaling molecules and transcriptional circuits with components that are dispensable for organogenesis but essential for regeneration. To supplement genetic screens, we designed a screen for chemical inhibitors of recovery and regeneration after damage by ionizing radiation, specifically X-rays. The primary screen used mutants in the Drosophila homologs of p53 and Checkpoint Kinase 1 to mimic the loss of p53 and deregulation of cell cycle checkpoints found in human cancers. The hits from the primary screen were counter-screened against wild-type larvae to select molecules that show differential effects on mutant over wild-type tissues. This screen found chemically distinct inhibitors of translation elongation, suggesting that this step in macromolecular synthesis is particularly important for tissues to survive radiation damage. One of these molecules, bouvardin (NSC259968), was further developed through structure-activity relationship analysis to produce a proprietary derivative called SVC112. Bouvardin and SVC112 are found to act on the human ribosome by a previously unknown mechanism. Discovery of bouvardin and development of SVC112 as an oncology agent toward human trials will be discussed in this chapter.
Insights
This study screened for chemicals that inhibit regeneration after X-ray damage in Drosophila, identifying translation elongation inhibitors like bouvardin and SVC112 as crucial for tissue survival and recovery.
Area of Science:
- Developmental Biology
- Molecular Biology
- Radiation Biology
Background:
- Drosophila melanogaster larvae possess significant organ regeneration capabilities.
- Conserved signaling molecules and transcriptional circuits are vital for regeneration, not organogenesis.
- Existing genetic screens are supplemented by chemical screens for regeneration inhibitors.
Purpose of the Study:
- To identify chemical inhibitors of recovery and regeneration after ionizing radiation (X-ray) damage.
- To investigate the role of specific molecular pathways in radiation survival and tissue repair.
- To discover novel compounds with potential therapeutic applications in oncology.
Main Methods:
- A chemical screen was designed using Drosophila mutants lacking p53 and Checkpoint Kinase 1 homologs.
- Primary screen identified inhibitors of recovery in mutant larvae.
- Counter-screening against wild-type larvae selected for differential effects, highlighting inhibitors of translation elongation.
Main Results:
- The screen identified chemically distinct inhibitors of translation elongation.
- Translation elongation is crucial for tissue survival following radiation damage.
- Bouvardin (NSC259968) and its derivative SVC112 were identified and further studied.
- Bouvardin and SVC112 exhibit a novel mechanism of action on the human ribosome.
Conclusions:
- Inhibitors of translation elongation are critical for tissue survival and regeneration after radiation injury.
- Bouvardin and its derivative SVC112 represent promising leads for cancer therapy, acting via a novel mechanism on human ribosomes.
- This research highlights the importance of translation regulation in radiation response and regenerative processes.
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