Sunday, June 1, 2025
6/1/2025
A novel therapeutic strategy to target mutant p53 - Project Summary/Abstract Mutation of the tumor suppressor gene TP53 occurs in more than half of human cancers. Mutant p53 is known to actively drives tumor progression, metastasis, and therapy resistance and thus, is considered as a promising target for cancer therapy. Our pilot studies showed that RNA-binding protein Rbm38, upon phosphorylation by CDK4 at serine 195, is able to interact with eIF4G and subsequently, enhances mutant p53 mRNA translation. We also found that a peptide derived from Rbm38, called Pep8SD, can bind to a pocket in eIF4G and thereby, disrupt the interaction between RBM38 and eIF4G, leading to decreased mutant p53 expression and subsequently, growth inhibition. Moreover, in silico screening identified a small molecule, called 094-63, which bound to the same pocket as Pep8SD peptide and elicited growth suppression by inhibiting mutant p53 expression. Furthermore, we found that compound 094-63 was able to attenuate mutant p53 expression in response to various chemo reagents. Notably, Rbm38, CDK4 and eIF4G are found to be over- expressed in triple negative breast cancers and associated with mutant p53 expression. Thus, we hypothesize that targeting the RBM38-eIF4G complex can be explored as a therapeutic strategy for triple negative breast cancer by specifically suppressing mutant p53 expression. To test this, the following three aims are proposed: (1) To determine how mutant p53 expression is regulated by the CDK4/6-RBM38-eIF4G axis and the role of mutant p53 as a target of CDK4/6 inhibitors to suppress mutant p53-expressing TNBCs; (2) To determine whether disruption of RBM38-eIF4G interaction suppresses mutant p53 expression and mutant p53-expessing tumors; (3) To determine whether compound 094-63 blocks DNA damage induction of mutant p53 and sensitizes mutant p53-expressing tumors to DNA-damaging drugs.
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