DIPG-59. Blood Brain Barrier (BBB) modulation using Cadherin peptides in the treatment of Diffuse Midline Glioma of the Pons (DMG-P)
Bibliographic record
Abstract
Abstract BACKGROUND: Diffuse midline glioma of the Pons (DMG-P) is the most common brainstem tumor of childhood and is universally fatal. The BBB is frequently intact in DIPG and restricts entry of systemically administered conventional and biological therapies. We have synthesized and validated synthetic cadherin peptides (HAV6, HAVN1) that cause transient opening of the BBB by preventing the dimerization of the extracellular membrane bound VE-Cadherin in the vascular endothelium. METHODS: We used DMG-P tumor conditioned media (TCM) and co-cultures in two in-vitro model systems (trans well inserts, Blood Brain Tumor Barrier microfluidics model (BBTB-DMG-P microchip)-using Human Brain microvascular endothelial cells (HBMVECs) / SF8628 (DMG-P PDX) and validated the in-vitro findings in a DMG-P orthotopic murine model using RA055. The permeability of different molecular weight markers [(Gd-DTPA, IRDye 800CW PEG, rhodamine 800 (R800)] were examined in presence / absence of HAV6 / HAVN1 peptides. RESULTS: The BBTB integrity is maintained in-vitro as evidenced by decreased permeability of all the agents across the barriers in the TCM / co-culture models. Addition of HAV6/ HAVN1 peptides in-vitro increased the permeability of all the agents across the barriers. The permeability of R800 increased in the presence of Elacridar (P-gp inhibitor). The BBB was intact in the DMG-P murine model, as evidenced by minimal Gd-DTPA contrast enhancement in T1 weighted MRI images. Administration of HAV6 / HAVN1 peptides resulted in Gd-DTPA contrast enhancement of the tumor at 5- and 10-minutes post injection. CONCLUSION: Our data confirms that the BBTB is intact in DMG-P and can be transiently modulated using synthetic cadherin peptides. Transient BBTB opening using synthetic peptides will help BBB non-penetrant chemotherapy drugs like Vincristine/Mitoxantrone and biological therapies to reach intra-tumoral therapeutic levels and improve therapeutic efficacy.
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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 | 0.000 |
| 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 | 0.000 |
| 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".