CNSC-54. LEVERAGING THERAPEUTIC MODULATORS OF NEUROPLASTICITY TO REPROGRAM GLIOBLASTOMA CELL FATES

Abstract BACKGROUND Glioblastomas (GBM) have the unique ability to hack neuronal plasticity. Neuroplasticity is controlled by brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB), for neuronal differentiation, survival and spinogenesis. To determine whether TrkB activity could pilot GBM cell fates, we screened total, single cell and spatial transcriptomics data from patient-derived glioblastoma stem cells (GSCs), preclinical and human samples. In parallel we used a curated library of drugs targeting TrkB including antidepressants and psychedelics, to control GBM cell fate. METHODS In silico: we generated total, single-cell and spatial transcriptomics data from mesenchymal (MES) and proneural (PN) patient-derived GSCs (N=10) and their in vivo analogues (N=9). In those, BDNF and TrkB gene expression and histological localization was verified and compared to published patient datasets (N=525). In vitro: on MES and PN GSCs, we verified TrkB and BDNF protein levels. We tested acute and chronic treatments with BDNF and/or five drugs targeting TrkB. Following treatments, GSC viability and sensitivity to temozolomide (TMZ) was quantified and tumor cell morphology analysed. RESULTS In GSCs, preclinical and clinical dataset, we identified TrkB upregulation in PN subtypes. BDNF was expressed in the tumor-adjacent brain tissue but not in GBM cells. In all GSCs, BDNF treatment increased proliferation and cell morphology complexity. To determine whether TrkB activation drove PN GSC differentiation, we used pharmacological modulators of TrkB. We identified lisuride (LSD analogue) increased PN GSCs proliferation, interfered with cell adhesion and reduced TMZ cytotoxicity. Conversely, lisuride increased TMZ cytotoxicity in MES GSC, indicating subtype-specific phenotypic responses. CONCLUSIONS These results provide a proof-of-concept for employing drugs targeting TrkB to harness GBM cell fate and chemosensitivity to TMZ. Such approaches may offer new avenues for combinatorial therapies targeting both GBM and its neural niche.