PT109, a novel multi-kinase inhibitor suppresses glioblastoma multiforme through cell reprogramming: Involvement of
Yang Yang1, Yalin Tu2, Junfeng Lu2
1School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China.
Abstract:
Glioblastoma multiforme (GBM) is the most prevalent type and lethal form of primary malignant brain tumor, accounting for about 40-50% of intracranial tumors and without effective treatments now. Cell reprogramming is one of the emerging treatment approaches for GBM, which can reprogram glioblastomas into non-tumor cells to achieve therapeutic effects. However, anti-GBM drugs through reprogramming can only provide limited symptom relief, and cannot completely cure GBM. Here we showed that PT109, a novel multi-kinase inhibitor, suppressed GBM's proliferation, colony formation, migration and reprogramed GBM into oligodendrocytes. Analysis of quantitative proteomics data after PT109 administration of human GBM cells showed significant influence of energy metabolism, cell cycle, and immune system processes of GBM-associated protein. Metabolomics analysis showed that PT109 improved the aerobic respiration process in glioma cells. Meanwhile, we found that PT109 could significantly increase the ratio of Pyruvate kinase M1/2 (PKM1/2) by reducing the level of polypyrimidine tract-binding protein 1 (PTBP1). Altogether, this work developed a novel anti-GBM small molecule PT109, which reprogramed GBM into oligodendrocytes and changed the metabolic pattern of GBM through the PTBP1/PKM1/2 pathway, providing a new strategy for the development of anti-glioma drugs.
Insights
A novel drug, PT109, reprograms deadly glioblastoma (GBM) brain tumors into non-cancerous cells. This multi-kinase inhibitor also alters GBM
Area of Science:
- Oncology
- Neuroscience
- Molecular Biology
Background:
- Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with limited treatment options.
- Cell reprogramming offers a promising therapeutic strategy for GBM by converting tumor cells into non-tumorigenic cell types.
- Current reprogramming-based therapies provide only symptomatic relief and do not offer a complete cure for GBM.
Purpose of the Study:
- To investigate the efficacy of PT109, a novel multi-kinase inhibitor, as a potential therapeutic agent against glioblastoma.
- To elucidate the mechanisms by which PT109 affects GBM cell behavior, including proliferation, migration, and cell fate.
- To explore the impact of PT109 on GBM cell metabolism and identify key molecular pathways involved.
Main Methods:
- Quantitative proteomics and metabolomics analyses were performed on human GBM cells treated with PT109.
- Assays were conducted to evaluate GBM cell proliferation, colony formation, and migration.
- Western blotting or similar techniques were used to assess protein levels, specifically PTBP1 and PKM1/2.
Main Results:
- PT109 significantly suppressed GBM proliferation, colony formation, and migration.
- PT109 induced the reprogramming of GBM cells into oligodendrocytes.
- PT109 treatment altered GBM cell metabolism, enhancing aerobic respiration and increasing the PKM1/2 ratio by reducing PTBP1 levels.
Conclusions:
- PT109 is a novel small molecule that demonstrates potent anti-GBM activity.
- PT109 reprograms glioblastoma cells into oligodendrocytes and modifies their metabolic profile via the PTBP1/PKM1/2 pathway.
- PT109 represents a promising new therapeutic strategy for glioblastoma treatment.
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