Sonic hedgehog signalling pathway in CNS tumours: its role and therapeutic implications

Abstract

CNS tumours encompass a diverse group of neoplasms with significant morbidity and mortality. The SHH signalling pathway plays a critical role in the pathogenesis of several CNS tumours, including gliomas, medulloblastomas and others. By influencing cellular proliferation, differentiation and migration in CNS tumours, the SHH pathway has emerged as a promising target for therapeutic intervention. Current strategies such as vismodegib and sonidegib have shown efficacy in targeting SHH pathway activation. However, challenges such as resistance mechanisms and paradoxical effects observed in clinical settings underscore the complexity of effectively targeting this pathway. Advances in gene editing technologies, particularly CRISPR/Cas9, have provided valuable tools for studying SHH pathway biology, validating therapeutic targets and exploring novel treatment modalities. These innovations have paved the way for a better understanding of pathway dynamics and the development of more precise therapeutic interventions. In addition, the identification and validation of biomarkers of SHH pathway activation are critical to guide clinical decision making and improve patient outcomes. Molecular profiling and biomarker discovery efforts are critical steps towards personalised medicine approaches in the treatment of SHH pathway-associated CNS tumours. While significant progress has been made in understanding the role of the SHH pathway in CNS tumorigenesis, ongoing research is essential to overcome current therapeutic challenges and refine treatment strategies. The integration of molecular insights with advanced technologies and clinical expertise holds great promise for developing more effective and personalised therapies for patients with SHH pathway-driven CNS tumours.

Keywords: Brain tumours; Molecular neuro-oncology; Neuro-genetics; Sonic Hedgehog signalling pathway.

Fig. 1

The SHH pathways in tumorigenesis and their types (canonical and non-canonical). Image was created with https://www.Biorender.com. CNS; Central Nervous System, CDON; Cell Adhesion Associated Oncogene Regulated; BOC; Butoxycarbonyl, GAS; Growth Arrest Specific, PTCH; Patched, SMO; Smoothened, SUFU; Suppressor of Fused; PKA; Protein Kinase A, CTD; C-Terminal Domain, CCNB; Cyclin B, GTPase; Guanosine Triphosphate, SHH; Sonic Hedgehog, RAS; Reticular Activating System, RAF; Rapidly Accelerated Fibrosarcoma, MEK; Mitogen-Activated Protein, ERK; Extracellular-Signal-Regulated kinase, PI3K; Phosphatidylinositol-3 Kinase, AKT; Protein Kinase B, mTOR; Mammalian Target of Rapamycin, TGF-β; Transforming Growth Factor Beta

Fig. 2

The interaction between the sonic hedgehog signalling pathway and other molecular pathways. Image was created with https://www.Biorender.com. SHH; Sonic Hedgehog, HH; Hedgehog, SUFU; Suppressor Of Fused, WNT; Wingless-Related Integrated Site, SMO; Smoothened, PTCH; Patched, GLI; Glioma Associated Oncogene, PKA; Protein Kinase A, sFRP; Secreted Frizzled-Related Protein, LRP; Low-Density Lipoprotein Receptor-Related Protein, GSK; Glycogen Synthase Kinase, APC; Antigen Presenting Cell, TCF; T-Cell Specific Transcription Factor, LEF; Lymphoid Enhancer-Binding Factor, VEGF; Vascular Endothelial Growth Factor, HES; Hairy And Enhancer Of Split, CNS; Central Nervous System, MB; Medulloblastoma, ADAM; A Disintegrin And Metalloproteinase, MAM; Mitochondrial-Associated Membranes, NICD; Notch Intracellular Domain, NECD; Notch Extracellular Domain, PIP; Phosphatidylinositol Phosphate, PDK; Pyruvate Dehydrogenase Kinase, AKT; Protein Kinase B, PI3K; Phosphatidylinositol 3-kinases, TSC; Tuberous Sclerosis Complex, Rheb; Ras Homolog Enriched In Brain, mTORC; Mammalian Target Of Rapamycin Complex, GDP; Guanosine Diphosphate, GTP; Guanosine Triphosphate