New Investigator Grant Awarded to John Prensner

All cancers hyperactivate certain genes to achieve their growth and aggressiveness. Yet, that gene activation can occur in different ways. For a gene to be functional, the genetic code of DNA must be converted into an intermediary called RNA, which itself is the template to produce the proteins that are the functional cell machinery. This second process is called RNA translation. While measuring the overall abundance of RNA is commonly used as a surrogate for cancer gene activation, this practice ignores the fact that RNA translation is an additional bottleneck: from that RNA, cancer cells can create too many or too few proteins, or even produce unintended proteins that may not exist in normal cells. In diffuse intrinsic pontine glioma, RNA translation appears particularly important for two reasons. First, many of the genes that drive DIPG cell growth are known to perturb normal RNA translation. Second, the underlying genetic cause of most DIPGs enables RNA translation to occur at genomic regions normally kept inaccessible, thereby generating unintended protein products. Thus, DIPG cells have an unexplored layer of biology that may result in either incorrect amounts of the proteins produced or incorrect regions of the genome producing proteins in the first place. Intriguingly, both scenarios may represent a new angle for treatment of DIPG, through drugs that target RNA translation in the first case and through activating the immune system to detect incorrect proteins in the second case. In this proposal, I hypothesize that this aberrant processing of RNA is an Achilles heel in DIPG that may be exploited for treatment. I will test this hypothesis using cutting-edge methods to measure how the cancer driver genes in DIPG alter the efficiency and output of RNA translation. I will focus on whether abnormal control of RNA translation results in increased therapeutic effect for inhibitors of this process, and I will determine whether abnormal sites of RNA translation generate unintended protein products that may be recognized by the immune system and therefore useful for immunotherapy. Completion of this work will be significant because it will be the first systematic investigation of abnormal RNA translation in DIPG and it will associate this process with different known DIPG driver genes. Ultimately, this work may suggest new avenues for treatment of DIPG and may lead to new therapeutics appropriate for testing in clinical trials.