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RAC1 regulates Sonic Hedgehog-medulloblastoma growth via GLI-mediated transcription
Nitish Jangde1, Mi Hye Lee1, Luz Ruiz1
1Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington, DC, USA.
Background:
Medulloblastoma (MB) is the most common malignant brain tumor of childhood, and current treatments cannot sufficiently inhibit tumoral growth, leptomeningeal dissemination, and metastasis. Ras-related C3 botulinum toxin substrate 1 (RAC1), a low molecular weight GTPase involved in cytoskeletal regulation and cell migration, is established to facilitate tumorigenesis in other neoplasia, but RAC1 is unexplored in MB and has no targeted therapies.
Methods:
We examined RAC1 activity in Sonic Hedgehog (SHH)-subtype MB using human and mouse Ptch1-/- cell models, RNAi knockdown, pharmacologic inhibition with GYS32661, transcript profiling, chromatin immunoprecipitation, and cytotoxicity assays in primary human astrocytes. We also determined the efficacy, brain penetration, and toxicity of GYS32661 in orthotopic spheroid Ptch1-/- mouse and rat models.
Results:
RAC1 activity was markedly increased in the MB tissue compared to the normal cerebellum. RAC1 depletion suppressed the proliferation and migration of SHH-MB cells. Mechanistically, RAC1 regulated GLI1 and GLI2 expression and bound the upstream loci of GLI1 and DNMT1, revealing a novel mechanism of SHH transcriptional regulation. GYS32661, a brain-permeable RAC1 inhibitor, was not toxic to normal astrocytes, suppressed SHH-MB tumor growth, and improved survival in vivo without toxicity in rats.
Conclusion:
RAC1 functions as a critical transcriptional regulator of SHH signaling and epigenetic mediators in medulloblastoma, highlighting its potential as a druggable target in SHH-dependent MB. Our findings also characterize the RAC1 inhibitor GYS32661 as a promising drug candidate for the treatment of SHH-MB.
Insights
Targeting RAC1, a key regulator of cell migration, shows promise for treating medulloblastoma (MB). The RAC1 inhibitor GYS32661 effectively reduced SHH-MB tumor growth and improved survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- Medulloblastoma (MB) is a common pediatric brain tumor with limited treatment options.
- Current therapies struggle to prevent tumor spread and metastasis.
- RAC1, a GTPase involved in cell migration, is implicated in other cancers but unexplored in MB.
Purpose of the Study:
- To investigate the role of RAC1 in SHH-subtype medulloblastoma.
- To evaluate the therapeutic potential of a novel RAC1 inhibitor, GYS32661.
Main Methods:
- Examined RAC1 activity in human and mouse MB models.
- Utilized RNAi knockdown, pharmacologic inhibition (GYS32661), and transcript profiling.
- Assessed GYS32661 efficacy, brain penetration, and toxicity in preclinical models.
Main Results:
- RAC1 activity was significantly elevated in MB tissue.
- RAC1 inhibition suppressed SHH-MB cell proliferation and migration.
- GYS32661 demonstrated efficacy in reducing tumor growth and improving survival in vivo without toxicity.
Conclusions:
- RAC1 is a critical regulator of SHH signaling and epigenetic mediators in medulloblastoma.
- RAC1 represents a druggable target for SHH-dependent MB.
- GYS32661 is a promising drug candidate for treating SHH-MB.
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