Sunday, May 18, 2025
5/18/2025
Angiogenin and plexin-B2 in therapeutic resistance and disease relapse of GBM - PROJECT SUMMARY Glioblastoma (GBM) is a fatal disease. The standard of care of GBM has not changed over decades. Tumor recurrence occurs universally and the recurred GBM lacks effective therapeutics. Glioma stem cells (GSCs), which are resistant to radio- and chemo-therapy, are a major cause of GBM recurrence. Identification and characterization of regulators and pathways that maintain the stemness properties of GSCs will help reveal new targets to eliminate, diminish, or exhaust GSCs to overcome therapeutic resistance and to prevent disease recurrence. We have discovered that angiogenin (ANG), a secreted ribonuclease, and its functional receptor plexin-B2 (PLXNB2), a single pass transmembrane protein, constitute a ligand-receptor pair that enhances the stemness of patient-derived GSCs by promoting small RNA biogenesis, in particular, the production of tRNA- derived stress-induced small RNAs (tiRNAs), and primarily the 5’tiRNAGly-GCC. PLXNB2 inhibition, by either gene knockout or specific monoclonal antibodies (mAbs), reduces the self-renewal ability and diminishes the tumorigenic capacity of patient-derived GSCs. A combinatorial treatment with PLXNB2 mAbs and temozolomide (TMZ) delayed the recurrence of GSC-drived orthotopic GBM and prolonged animal survival as compared to TMZ monotherapy. PLXNB2 mAb therapy was found to reduce the intra-tumor level of tiRNAs including 5’tiRNAGly-GCC. There was an inverse correlation between the 5’tiRNAGly-GCC level in the tumor and animal survival. We therefore propose to characterize the ANG-PLXNB2-tiRNA axis as a novel regulatory pathway that maintains the stemness properties of GSCs and that can be targeted to prevent or delay GBM recurrence upon chemo- and radio-therapy. Specific aim 1 is to characterize the function of the ANG/PLXNB2 axis in regulation of GSC properties and GBM recurrence. We will 1) examine the role of ANG/PLXNB2 in proneural type and mesenchymal type GSCs to understand if the regulatory function is limited to a specific GSC type or if it is more broadly applicable; 2) differentiate the function of ANG and semaphorin 4C, the other high affinity ligand of PLXNB2, in GSCs. Specific aim 2 is to elucidate the mechanism by which ANG/PLXNB2 regulates GSC stemness and GBM recurrence. We will 1) examine the function and mechanism of 5’tiRNAGly-GCC in regulating GSC stemness and GBM chemoresistance; 2) examine the functions of other tiRNA species that are significantly regulated by ANG/PLXNB2; 3) conduct proteomics studies to identify tiRNA-regulated proteins, and characterize how they mediate GSC stemness and chemoresistance. We expect that we will be able to demonstrate ANG and PLXNB2 as novel GSC regulators, characterize the molecular mechanism by which they maintain GBM stemness, and establish ANG-PLXNB2-tiRNA axis as a targetable pathway for the purpose of preventing GBM recurrence upon radio- and chemo-therapy.
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