A peptide encoded by upstream open reading frame ofbinds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice.

in Science translational medicine by Fanying Li, Kailin Yang, Xinya Gao, Maolei Zhang, Danling Gu, Xujia Wu, Chenfei Lu, Qiulian Wu, Deobrat Dixit, Ryan C Gimple, Yongping You, Stephen C Mack, Yu Shi, Tiebang Kang, Sameer A Agnihotri, Michael D Taylor, Jeremy N Rich, Nu Zhang, Xiuxing Wang

TLDR

  • The study found that a protein called MPEP is made from a part of the MYC gene that is not usually used to make the MYC protein. MPEP is made from a part of the MYC gene called an upstream open reading frame (uORF). MPEP is made from the first 114 amino acids of the MYC protein. MPEP is secreted and promotes the growth of tumors in mice. The study also found that MPEP promotes the growth of tumors in people with glioblastoma. The study suggests that targeting MPEP could be a new way to treat glioblastoma.

Abstract

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the varianttranscript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF). Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.

Overview

  • The study investigates the role of MYC in promoting tumor growth in human glioblastomas. The study shows that a variant transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF). Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. The study aims to identify a new therapeutic strategy for glioblastoma by targeting MPEP through genetic ablation or an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor. The primary objective of the study is to demonstrate the clinical relevance of MPEP in glioblastoma and its potential as a therapeutic target.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions. The study identifies that secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of TRKB, which induces downstream AKT-mTOR signaling. The study also shows that overexpression of MPEP in surgical glioblastoma specimens predicts a poor prognosis, supporting its clinical relevance. The key findings of the study are that tumor-specific translation of a-associated uORF promotes glioblastoma growth and that targeting MPEP through genetic ablation or an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor could be a new therapeutic strategy for glioblastoma.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies a new therapeutic strategy for glioblastoma by targeting MPEP through genetic ablation or an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor. The study also highlights the clinical relevance of MPEP in glioblastoma and its potential as a therapeutic target. Future research directions could include further investigation of the mechanisms underlying MPEP-mediated tumor growth and the development of more specific and targeted therapies for glioblastoma.
Read Full Article