SHH inhibitors for the treatment of medulloblastoma

Abstract

Medulloblastoma is the most common malignant brain tumor of childhood. It is currently stratified into four molecular variants through the advances in transcriptional profiling. They include: wingless, sonic hedgehog (SHH), Group III, and Group IV. The SHH group is characterized by constitutive activation of the SHH signaling pathway, and genetically characterized by mutations in patched homolog 1 (PTCH1) or other downstream pathway mutations. SHH inhibitors have become of great clinical interest in treating SHH-driven medulloblastoma. Many inhibitors are currently in different stages of development, some already approved for other SHH-driven cancers, such as basal cell carcinoma. In vitro and in vivo medulloblastoma studies have shown efficacy and these findings have been translated into Phase I and II clinical trials. In this review, we present an overview of SHH medulloblastoma, as well as a discussion of currently available SHH inhibitors, and the challenges associated with their use.

Keywords:

• basal cell carcinoma
• gorlin syndrome
• medulloblastoma
• smoothened
• sonic hedghog
• vismodegib

Acknowledgement

The authors would like to thank Gregory Klimowicz who assisted in the construction of Figure 1.

Financial and competing interests disclosure

RJ Packer is on the DSMB (Data Safety Monitoring Board) of Genentech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Medulloblastoma is malignant small blue cell embryonal tumor of the cerebellum and is the most common malignant brain tumor during childhood.

• Medulloblastoma is no longer considered one disease; at least four core molecular variants have been discovered: wingless (WNT), sonic hedgehog (SHH), group III and IV.

• The SHH group, characterized by constitutive activation of the (SHH) signaling pathway, is often histologically desmoplastic and usually arises from the cerebellar hemisphere.

• Current medulloblastoma treatment is not molecularly driven, although SHH tumors were among the first medulloblastoma tumors to be targeted.

• The naturally occurring drug cyclopamine was one of the first agents discovered to have inhibitory activity of SHH pathway by selectively binding to SMO.

• Multiple cyclopamine derivatives that suppress SHH signaling are in different phases of development and include: saridegib (IPI-926), vismodegib (GDC-0449), erismodegib (LDE-225), TAK-441, XL-139 (BMS-833923), PF-04449913 and PF-5274857.

• SHH inhibitor challenges include developmental side effects as well as primary and acquired resistance.

• Alternative approaches to inhibit SHH and overcome resistance are being explored using itraconazole, arsenic trioxide, mebendazole, BET bromodomain inhibitors and foretinib.