Summary: Indirubin, a natural compound derived from indigo plants and long used in traditional Chinese medicine, has been formulated for injection and shown to extend survival in mouse models of glioblastoma by targeting tumor growth and immunosuppressive pathways.
Source: Brown University
A recent study reveals how a drug based on a traditional Chinese medicine compound can act against aggressive brain tumors in mice, offering a promising direction for glioblastoma therapy development.
Published in Cell Reports Medicine, the study demonstrates that a deliverable formulation of the indirubin derivative 6′-bromoindirubin-3′-acetoxime (abbreviated BiA) improves survival in immunocompetent mouse models of malignant glioblastoma (GBM). The researchers also developed a nanoparticle formulation, PPRX-1701, that makes the compound easier to administer and brings this therapeutic approach closer to potential clinical testing.
“This compound is interesting because it hits several key features of glioblastoma at once,” said Sean Lawler, lead author and associate professor of pathology and laboratory medicine at Brown University. “GBM often evades single-target treatments, so a therapy that engages multiple mechanisms simultaneously may be more effective.”
The collaborative research team included investigators from Brown’s Legorreta Cancer Center and School of Engineering, neurosurgery at Brigham and Women’s Hospital/Harvard Medical School, and the biomedical companies Phosphorex, Inc. and Cytodigm, Inc.
Glioblastoma is the most common and aggressive primary brain tumor in adults. Current standard care—surgery, radiation and chemotherapy—can alleviate symptoms and modestly extend life but does not cure the disease. New therapeutic strategies that improve survival and that can be combined with existing treatments are urgently needed.
Indirubin is a bioactive molecule found in indigo plants and a component of the traditional Chinese medicine formulation Dang Gui Long Hui Wan, which has been used historically in some blood-related disorders. Laboratory derivatives of indirubin have demonstrated anti-cancer activity through multiple mechanisms, including cell-cycle arrest and modulation of signaling pathways.
Earlier work from Lawler’s group showed that indirubin derivatives could slow glioblastoma growth in mice, but questions remained about how the compound worked and how to deliver it effectively to tumor tissue. Some derivatives were difficult to handle, complicating dose optimization and administration.
Phosphorex, a Massachusetts-based biomedical company specializing in formulation technologies, provided a patented injectable formulation of the indirubin derivative BiA that the investigators evaluated in this study. Using a nanoparticle delivery system, PPRX-1701, the team was able to deliver BiA more effectively to intracranial tumors in mice.
In preclinical experiments, PPRX-1701 not only reduced tumor cell proliferation and slowed tumor growth—confirming prior findings—but also produced beneficial changes in the tumor immune environment. The formulation reduced expression of immunosuppressive genes and proteins, including indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) pathway that helps tumors suppress anti-tumor immunity.
Transcriptomic analyses in the study showed that BiA downregulates immune-related genes associated with tumor-mediated immune suppression. In vitro experiments demonstrated that BiA blocks interferon-γ–induced IDO1 protein expression and enhances T cell–mediated killing of glioblastoma stem-like cells in co-culture models. In vivo, PPRX-1701 reached intracranial GBM sites and significantly improved survival in immunocompetent mouse models.
“The drug affected the immune system in a way that suggests it could complement clinical immunotherapies,” Lawler said. His laboratory is continuing to explore how BiA interacts with standard treatments like chemotherapy and radiation, with the goal of designing clinical trials for people with glioblastoma.
Given the limited progress in extending meaningful survival for GBM patients over the past two decades, new approaches that combine direct tumor suppression with immunomodulatory effects are particularly valuable. The dual action of BiA—tumor growth inhibition plus reversal of immunosuppressive mechanisms—supports further investigation and potential translation.
The authors emphasize that these findings are preclinical and that additional studies are needed to define optimal combinations, dosing, safety and delivery methods before human trials can begin. Still, the results provide a strong rationale to advance PPRX-1701 and similar formulations as candidate therapies that could be integrated with existing glioblastoma treatment strategies.
About this brain cancer research news
Author: Press Office
Source: Brown University
Contact: Press Office – Brown University
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Original Research: Open access.
“PPRX-1701, a nanoparticle formulation of 6′-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models” by Mykola Zdioruk et al. Cell Reports Medicine
Abstract
PPRX-1701, a nanoparticle formulation of 6′-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models
Highlights
- PPRX-1701 is a deliverable nanoparticle formulation of 6-bromoindirubin-3′-acetoxime (BiA)
- BiA inhibits IDO1 expression and increases CD8+ T cell infiltration in GBM mouse models
- Preclinical data support further investigation and potential clinical translation
Summary
Derivatives of the traditional Chinese medicine compound indirubin have demonstrated anti-cancer potential through multiple mechanisms. This study examines BiA’s effects on immunosuppressive pathways in glioblastoma and evaluates the efficacy of a nanoparticle injectable, PPRX-1701, in immunocompetent mouse GBM models.
Molecular analyses indicate that BiA downregulates immune-related genes, notably IDO1, which plays a central role in the Trp-Kyn-AhR immunosuppressive cascade. BiA blocks IFNγ-induced IDO1 protein expression in vitro and enhances T cell–mediated tumor killing in GBM stem-like cell co-cultures. Importantly, the PPRX-1701 formulation reaches intracranial tumors and significantly extends survival in vivo in immunocompetent GBM models.
Overall, these results show that BiA can improve survival in murine GBM models by targeting key immunotherapeutic pathways and that it can be effectively delivered via the PPRX-1701 nanoparticle formulation. Continued preclinical evaluation will inform potential clinical trial design and combination strategies with existing therapies.