Modulation of blood-tumor barrier transcriptional programs improves intratumoral drug delivery and potentiates chemotherapy in GBM
Efficient drug delivery to glioblastoma (GBM) is a major obstacle as the blood-brain barrier (BBB) and the blood-tumor barrier (BTB) prevent passage of the majority of chemotherapies into the brain. Here, we identified a transcriptional 12-gene signature associated with the BTB in GBM. We identified CDH5 as a core molecule in this set and confirmed its expression in GBM vasculature using transcriptomics and immunostaining of patient specimens. The indirubin-derivative, 6-bromoindirubin acetoxime (BIA), down-regulates CDH5 and other BTB signature genes, causing endothelial barrier disruption in vitro and in murine GBM xenograft models. Treatment with BIA increased intratumoral cisplatin accumulation and potentiated DNA damage by targeting DNA repair pathways. Last, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved cisplatin efficacy in murine GBM. Our work reveals potential targets of the BTB and the bifunctional properties of BIA as a BTB modulator and a potentiator of chemotherapy, supporting its further development.
Authors
- Sean Lawler (ORCID: https://orcid.org/0000-0002-1633-2339)
- Paul Bertone (ORCID: https://orcid.org/0000-0001-5059-4829)
- Kelsey E. Huntington (ORCID: https://orcid.org/0000-0002-5810-8220)
- Choi‐Fong Cho (ORCID: https://orcid.org/0000-0003-1473-9773)
- Michal O. Nowicki (ORCID: https://orcid.org/0000-0002-5807-0007)
- Alexander S. Brodsky (ORCID: https://orcid.org/0000-0001-7357-5153)
- Jorge L. Jimenez-Macias (ORCID: https://orcid.org/0000-0001-6002-8222)
- Katherine E. Manz (ORCID: https://orcid.org/0000-0002-8225-9168)
- Noe B. Mercado (ORCID: https://orcid.org/0000-0001-7769-7326)
- Philippa Vaughn-Beaucaire (ORCID: https://orcid.org/0009-0000-7362-1869)
- Zheyun Xu (ORCID: https://orcid.org/0000-0002-1101-7014)
- Michael Punsoni
- Kurt D. Pennell (ORCID: https://orcid.org/0000-0002-5788-6397)
- Jason Hong (ORCID: https://orcid.org/0000-0002-5062-8926)
- Jasmine Clark
- Bin Wu (ORCID: https://orcid.org/0000-0001-5691-7967)
- William Hawkins
- Bogdan I. Fedeles (ORCID: https://orcid.org/0000-0001-5252-826X)
- Mykola Zdioruk (ORCID: https://orcid.org/0000-0002-4275-2724)
- Andrea Barbara Schmidt (ORCID: https://orcid.org/0000-0003-2940-6613)
- Weiyi Li (ORCID: https://orcid.org/0000-0001-9060-0883)
- Jacqueline Real
- Michael Sun
- Megan Forrest
- Theresa Logan
- Ayush Bharati
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Brown University (US)
- Combat Capabilities Development Command Soldier Center (US)
- Center for Environmental Health (US)
- Xerox (France) (FR)
- Harvard Stem Cell Institute (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1126/sciadv.adr1481
- Citations
- 7
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 11.38