Scientists developed a new drug, GR-28, that inhibits a protein called SCP1. This leads to the degradation of another protein, REST, which promotes the growth of brain tumor cells. Combining GR-28 with a lipid metabolism inhibitor shows synergistic effects in killing tumor cells.
Background
Glioblastoma (GBM) is a highly aggressive and fatal brain tumor with limited treatment options. Current therapies, such as surgery, radiation, and chemotherapy, often prove ineffective due to the tumor’s aggressive growth, resistance to treatment, and propensity to recur. The development of novel therapeutic strategies is crucial to improve patient outcomes.
Targeting specific molecular pathways involved in GBM progression has emerged as a promising approach. However, directly targeting transcription factors, which play crucial roles in regulating gene expression and cellular processes, with small molecule inhibitors has historically been challenging. Additionally, GBM cells often develop resistance mechanisms, such as genetic mutations and metabolic rewiring, which further hinder the efficacy of targeted therapies.
Technology description
This technology involves the development of small molecule compounds, specifically GR-28, designed to inhibit the REST protein. REST is a transcriptional repressor implicated in the proliferation of glioblastoma cells, and its degradation can potentially inhibit cancer stem cell proliferation. GR-28 works by inhibiting SCP1, a phosphatase that dephosphorylates and stabilizes REST, thereby promoting REST degradation. This leads to the derepression of REST-silenced genes and induces cell death in high-REST glioblastoma cells.
This technology is differentiated due to its dual-targeting approach. While GR‑28 effectively targets and inhibits REST, the research revealed that some glioblastoma cells could compensate for REST loss by rewiring their lipid metabolism. This led to the discovery that combining GR-28 with Triacsin C, a fatty acid metabolism inhibitor, resulted in synergistic therapeutic effects.
This combination therapy effectively countered the compensatory mechanism and exhibited a significant increase in glioblastoma cell death with limited hepatotoxicity. This dual-targeting approach offers a promising strategy for treating high-REST glioblastomas while minimizing adverse effects.
Benefits
- Targeted therapy for glioblastoma: The invention focuses on developing small molecule compounds that specifically target REST, a protein overexpressed in glioblastoma cells and associated with poor prognosis. This targeted approach aims to inhibit tumor growth while minimizing side effects on healthy cells.
- Inhibition of cancer stem cell proliferation: REST is crucial for cancer stem cell self-renewal. By targeting REST, the invention aims to inhibit the proliferation of these treatment-resistant cells, potentially leading to more effective glioblastoma treatment.
- Overcoming treatment resistance: The invention addresses the challenge of treatment resistance in glioblastoma by identifying and targeting a compensatory mechanism involving fatty acid metabolism. Combining the REST inhibitor GR-28 with a fatty acid metabolism inhibitor (Triacsin C) demonstrated synergistic therapeutic effects, effectively killing glioblastoma cells.
- Reduced neurological side effects: Targeting REST may have fewer neurological side effects compared to conventional chemotherapy because REST is not expressed in post-mitotic neurons.
- Improved selectivity and therapeutic window: The combination therapy using GR-28 and Triacsin C exhibited limited hepatotoxicity, demonstrating improved selectivity for glioblastoma cells over healthy liver cells. This selectivity is crucial for developing safer and more effective treatments.
Commercial applications
- Glioblastoma treatment
- Cancer stem cells
- Tumor regression
- REST inhibitors
- SCP1 inhibitors
Patent link
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-024-01879-0