Author: Chiocca, E Antonio ; Finkelberg, Tomer ; Zdioruk, Mykola ; Ling, Alexander L ; Li, Weiyi ; Wu, Bin ; Lawler, Sean E ; Koch, Marilin S ; Pennell, Kurt D ; Manz, Katherine E ; Takeda, Yuji ; Boucher, Paul ; Piranlioglu, Raziye ; Jimenez-Macias, Jorge-Luis ; Nowicki, Michal Oskar

Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.

Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM

Article

Author: Pennell, Kurt D ; Forrest, Megan ; Hawkins, William ; Pennell, Kurt D. ; Lawler, Sean E ; Fedeles, Bogdan I ; Manz, Katherine E ; Clark, Jasmine ; Vaughn-Beaucaire, Philippa ; Nowicki, Michal O. ; Schmidt, Andrea ; Brodsky, Alexander S ; Hong, Jason ; Brodsky, Alexander S. ; Manz, Katherine E. ; Sun, Michael ; Real, Jacqueline ; Zdioruk, Mykola ; Logan, Theresa ; Huntington, Kelsey ; Mercado, Noe ; Xu, Zheyun ; Jimenez-Macias, Jorge L. ; Jimenez-Macias, Jorge L ; Nowicki, Michal O ; Li, Weiyi ; Bharati, Ayush ; Fedeles, Bogdan I. ; Wu, Bin ; Lawler, Sean E. ; Cho, Choi-Fong

AbstractGlioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroidsin vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenografts and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma	Preclinical	US	The Brigham & Women's Hospital, Inc.	-

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