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Evaluation of retinoic acid therapy for OTX2-positive medulloblastomas
Renyuan Bai1, I-Mei Siu, Betty M Tyler
1Department of Neurosurgery, Johns Hopkins University, CRB II Rm. 257, 1550 Orleans Street, Baltimore, MD 21231, USA.
Abstract:
The homeobox transcription factor OTX2 plays an essential role during embryonic brain development. It is normally silenced in the adult brain, but is overexpressed by genomic amplification or other mechanisms in the majority of medulloblastomas (MBs). Retinoic acids (RAs) can suppress OTX2 expression and inhibit MB growth. In this study, 9-cis RA most potently inhibited MB cell growth. 9-cis RA functions through the downregulation of OTX2 expression, which subsequently induces neuronal differentiation of OTX2-expressing cells. Treatment with 9-cis RA reduced the growth of D425 flank xenograft tumors in mice. In an intracranial model, however, MB tumors showed resistance to 9-cis RA treatment, and we implicated fibroblast growth factor (FGF) as a potential mediator of resistance to RA therapy. These findings suggest a mechanism for RA-mediated anti-tumor effect on OTX2-positive MB cells and indicate that therapeutic targeting of OTX2 might be effective if FGF pathway-mediated resistance can be overcome.
Insights
Retinoic acids (RAs) inhibit medulloblastoma (MB) growth by suppressing OTX2. While 9-cis RA showed efficacy in xenografts, intracranial MB tumors developed resistance, potentially mediated by fibroblast growth factor (FGF).
Area of Science:
- Neuroscience
- Developmental Biology
- Cancer Biology
Background:
- OTX2 transcription factor is crucial for embryonic brain development.
- OTX2 is overexpressed in most medulloblastomas (MBs), driving tumor growth.
- Retinoic acids (RAs) can suppress OTX2 and inhibit MB proliferation.
Purpose of the Study:
- To investigate the efficacy of 9-cis retinoic acid (RA) in suppressing OTX2 and inhibiting medulloblastoma (MB) growth.
- To explore mechanisms of resistance to RA therapy in an intracranial MB model.
Main Methods:
- Treatment of MB cells and xenografts with 9-cis RA.
- Analysis of OTX2 expression and neuronal differentiation.
- Investigation of fibroblast growth factor (FGF) involvement in RA resistance.
Main Results:
- 9-cis RA potently inhibited MB cell growth and OTX2 expression.
- 9-cis RA induced neuronal differentiation in OTX2-expressing MB cells.
- MB tumors exhibited resistance to 9-cis RA in an intracranial model, with FGF implicated as a resistance mediator.
Conclusions:
- RA-mediated suppression of OTX2 induces anti-tumor effects in OTX2-positive MB cells.
- Therapeutic targeting of OTX2 is a potential strategy for MB treatment.
- Overcoming FGF pathway-mediated resistance is crucial for effective RA therapy in MB.
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