Targeted treatment for sonic hedgehog-dependent medulloblastoma

Abstract

Novel treatment options, including targeted therapies, are needed for patients with medulloblastoma (MB), especially for those with high-risk or recurrent/relapsed disease. Four major molecular subgroups of MB have been identified, one of which is characterized by activation of the sonic hedgehog (SHH) pathway. Preclinical data suggest that inhibitors of the hedgehog (Hh) pathway could become valuable treatment options for patients with this subgroup of MB. Indeed, agents targeting the positive regulator of the pathway, smoothened (SMO), have demonstrated efficacy in a subset of patients with SHH MB. However, because of resistance and the presence of mutations downstream of SMO, not all patients with SHH MB respond to SMO inhibitors. The development of agents that target these resistance mechanisms and the potential for their combination with traditional chemotherapy and SHH inhibitors will be discussed. Due to its extensive molecular heterogeneity, the future of MB treatment is in personalized therapy, which may lead to improved efficacy and reduced toxicity. This will include the development of clinically available tests that can efficiently discern the SHH subgroup. The preliminary use of these tests in clinical trials is also discussed herein.

Keywords: expression profiling; hedgehog; medulloblastoma; targeted therapy.

Fig. 1.

The hedgehog signaling pathway. (A) In the absence of hedgehog (Hh) ligands, the transmembrane receptor patched (PTCH) inhibits entry of the G-protein-coupled receptor-like transmembrane signal transducer smoothened (SMO). Glioma-associated oncogene (GLI) transcription factors are sequestered in the cytoplasm in a complex containing the negative regulator suppressor of fused (SUFU). GLIs are processed into a transcriptional repressor form or degraded. (B) Hh signaling is activated when Hh binds to PTCH on the cell surface. Both molecules are then internalized (and PTCH is degraded), allowing SMO to activate downstream signaling events. The GLI transcription factors are released from SUFU and processed into their activating forms. Activated GLIs translocate into the nucleus and promote transcription of Hh pathway target genes.

Fig. 2.

Frequency of the sonic hedgehog subgroup of medulloblastoma by age. (A) Frequency of the sonic hedgehog (SHH) subgroup of medulloblastoma (MB) in males and females by age group. (B) Incidences of the wingless (WNT), SHH, group 3, and group 4 subgroups of MB in infants, children, and adults. Figure adapted from Kool M, et al. Acta Neuropathol. 2012; 123(4): 473–484, under terms of the Creative Commons Attribution License.