CNSC-38. TARGETING UNC5B INDUCES BLOOD-BRAIN BARRIER PERMEABILITY AND IMPROVES CHEMOTHERAPY DELIVERY AND EFFICACY IN GLIOBLASTOMA
Bibliographic record
Abstract
Abstract The blood-brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) from toxins and pathogens while maintaining CNS homeostasis and function. However, this tightly regulated impermeability also poses a major challenge for delivery of therapeutic agents during CNS pathologies, including glioblastoma (GBM), the most common and aggressive primary brain tumor. GBM is associated with a median survival of 12–15 months post-diagnosis and a five-year survival rate of less than 5%. Thus, developing strategies to safely and effectively overcome the restrictive nature of the BBB remains a major challenge and key objective in neuro-oncology. We have identified Unc5B as a key regulator of BBB integrity via modulation of the Wnt/β-catenin pathway. Systemic administration of an anti-Unc5B blocking antibody induced transient, size-selective BBB opening, suggesting that anti-Unc5B could serve as a transformative tool in neuropharmacology, enabling controlled CNS drug delivery. In this study, our main goal was to assess the therapeutic potential and mechanistic basis of anti-Unc5B-mediated BBB modulation in glioblastoma. To achieve this, we first characterized expression of the Unc5B receptor and associated pathways in GBM endothelial cells using single-cell RNA sequencing and RT-PCR of patient-derived GBM samples. We further utilized iDISCO/LSFM and two-photon live imaging to investigate the spatial distribution and temporal dynamics of BBB modulation following anti-Unc5B administration. Mechanistically, we found that anti-Unc5B treatment promotes ubiquitination, internalization, and degradation of Claudin-5 (Cldn5), mediated by E3 ubiquitin ligase Siah1. Importantly, we demonstrated for the first time that anti-Unc5B-induced BBB opening enhances delivery of both conventional chemotherapies, such as doxorubicin and temozolomide, and targeted therapies, including the EGFRvIII-specific inhibitor osimertinib, in GBM-bearing mice. This enhanced delivery resulted in reduced tumor burden, increased tumor cell apoptosis, and improved survival. These findings represent the first preclinical validation of anti-Unc5B monoclonal blocking antibody in glioblastoma models and highlight its potential to improve drug delivery and therapeutic efficacy in brain tumors.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".