John Prensner, MD, PhD

Atypical teratoid/rhabdoid tumor (ATRT) is a rare and aggressive central nervous system tumor that typically forms in the cerebellum or brain stem, areas of the brain responsible for movement, balance, and basic body functions. ATRT primarily affects infants and young children, with the majority of cases diagnosed by age 3. It is one of the most common malignant brain tumors in children under 3, and also one of the deadliest: over half of children diagnosed with ATRT do not survive. Current treatments include surgery, when possible, and chemotherapy, which can be highly toxic in these young patients. The development of new treatment approaches that more specifically and safely target cancer cells is critical for children with ATRT.

John Prensner, MD, PhD is a CureSearch Young Investigator Awardee at the University of Michigan working to develop a deeper understanding of the root causes of pediatric brain tumors, in hopes of identifying novel targets for future therapies. His work includes the study of small open reading frames (sORFs), which are tiny segments of DNA that produce small proteins, or microproteins. These microproteins have been shown to play essential roles in cellular processes, such as regulating gene expression, cell signaling, and response to cellular stress. In cancer cells, the normal process of making proteins can become dysregulated, activating “non-canonical” sORFs that in turn produce microproteins that help cancer cells thrive.

While ATRT contains few known gene targets for treatment, Dr. Prensner believes that sORFs represent an untapped layer of ATRT biology that may inform future therapeutic strategies. He hypothesizes that ATRT cells rely on specific microproteins produced by sORFs to support their growth, and that these proteins could represent novel therapeutic targets for ATRT. In his CureSearch funded work, he will further characterize the role that sORFs play in ATRT and identify those that are critical for cancer cell survival. Additionally, he will explore the potential of certain sORFs to predict if ATRT cells will respond to anti-ribosome targeting therapies – treatments that block a cell’s protein making machinery, reducing the growth and spread of cancer cells.

Dr. Prensner’s work could significantly expand the range of targetable genes in ATRT, paving the way for more personalized treatments. His findings may establish sORFs as biomarkers to identify children with ATRT who might benefit from specific ribosome-targeting therapies. Additionally, it could support a clinical trial of omacetaxine, an FDA-approved ribosome targeting therapy already in use in adults, for children with brain tumors such as ATRT.