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MCM2 and Carbonic Anhydrase 9 Are Novel Potential Targets for Neuroblastoma Pharmacological Treatment
Patrizia Garbati1, Raffaella Barbieri1, Davide Cangelosi2
1IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.
Abstract:
To overcome the lack of effective pharmacological treatments for high-risk neuroblastoma (HR-NB), the development of novel in vitro and in vivo models that better recapitulate the disease is required. Here, we used an in vitro multiclonal cell model encompassing NB cell differentiation stages, to identify potential novel pharmacological targets. This model allowed us to identify, by low-density RT-PCR arrays, two gene sets, one over-expressed during NB cell differentiation, and the other up-regulated in more malignant cells. Challenging two HR-NB gene expression datasets, we found that these two gene sets are related to high and low survival, respectively. Using mouse NB cisplatin-treated xenografts, we identified two genes within the list associated to the malignant stage (MCM2 and carbonic anhydrase 9), whose expression is positively correlated with tumor growth. Thus, we tested their pharmacological targeting as potential therapeutic strategy. We measured mice survival and tumor growth rate after xenografts of human NB treated with cisplatin in the presence of MCM2/carbonic anhydrase 9 inhibitors (ciprofloxacin and acetazolamide). MCM2 or carbonic anhydrase 9 inhibition significantly increased cisplatin activity, supporting their possible testing for NB therapy.
Insights
Novel therapeutic targets were identified for high-risk neuroblastoma (HR-NB). Inhibiting MCM2 or carbonic anhydrase 9 enhanced cisplatin treatment efficacy in preclinical models, offering new hope for neuroblastoma therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- High-risk neuroblastoma (HR-NB) lacks effective pharmacological treatments.
- Development of advanced in vitro and in vivo models is crucial for identifying new therapeutic strategies.
- Understanding gene expression dynamics during NB cell differentiation and malignancy is key.
Purpose of the Study:
- To identify novel pharmacological targets for HR-NB.
- To evaluate the therapeutic potential of targeting specific genes associated with NB malignancy.
- To assess the efficacy of combined treatment with existing chemotherapy and novel target inhibitors.
Main Methods:
- Utilized a multiclonal in vitro cell model reflecting NB differentiation stages.
- Employed low-density RT-PCR arrays to identify differentially expressed gene sets.
- Analyzed HR-NB gene expression datasets and validated findings in mouse cisplatin-treated xenografts.
- Pharmacologically inhibited MCM2 and carbonic anhydrase 9 in combination with cisplatin in xenograft models.
Main Results:
- Identified gene sets associated with NB cell differentiation and malignancy.
- Two genes, MCM2 and carbonic anhydrase 9, were linked to malignant stages and positively correlated with tumor growth.
- Inhibition of MCM2 or carbonic anhydrase 9 significantly enhanced cisplatin's anti-tumor activity in vivo.
- Increased mice survival and reduced tumor growth rates were observed with combination therapy.
Conclusions:
- MCM2 and carbonic anhydrase 9 represent promising therapeutic targets for HR-NB.
- Targeting MCM2 or carbonic anhydrase 9 in combination with cisplatin shows potential for improving neuroblastoma treatment outcomes.
- These findings support further investigation and clinical testing of this therapeutic strategy for neuroblastoma patients.
