Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis
Annika Sprüssel1,2, Takayoshi Suzuki3,4, Naoki Miyata5
1Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
Journal of Clinical Medicine
|October 26, 2024
Summary
The KDM1A inhibitor NCL-1 shows promise for treating neuroblastoma by reducing tumor cell growth and differentiation. This dual action targets aggressive tumors and their vascular support, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- KDM1A histone demethylase is crucial for cell proliferation and differentiation.
- Deregulation of KDM1A is implicated in human cancers, including neuroblastoma.
- High KDM1A expression in neuroblastoma correlates with poor prognosis, suggesting therapeutic potential.
Purpose of the Study:
- To evaluate the efficacy of NCL-1, a KDM1A-specific inhibitor, in preclinical neuroblastoma models.
- To investigate the effects of KDM1A inhibition on neuroblastoma cell phenotypes and tumor growth.
Main Methods:
- Tested NCL-1 in four neuroblastoma cell lines and a patient-representative cell model.
- Assessed NCL-1 effects on cell proliferation, viability, differentiation markers, and xenograft tumor growth in mice.
- Evaluated NCL-1's impact on endothelial cell function in vitro.
Main Results:
- NCL-1 effectively inhibited KDM1A activity, mimicking siRNA knockdown effects.
- KDM1A inhibition reduced proliferation and viability while inducing neuronal differentiation markers.
- NCL-1 treatment decreased tumor growth, inhibited proliferation, reduced vessel density, and impaired blood vessel formation in vivo and in vitro.
Conclusions:
- Targeting KDM1A with NCL-1 offers a dual therapeutic strategy against aggressive neuroblastomas.
- This approach shifts tumor cells towards a less aggressive phenotype and hinders tumor vascularization.
- NCL-1 demonstrates potential as a novel treatment for neuroblastoma.
