Novel peptide-based drugs for the treatment of sonic hedgehog-dependent medulloblastoma

Correspondence: Dr. Raelene Endersby, Brain Tumour Research Program, or Dr. Paul Watt, Phylogica Ltd, Telethon Kids Institute, 100 Roberts Road, Subiaco WA, 6008, Australia. E-mail: raelene.endersby@.au, paulw@. *PBD and NM contributed equally to this work. #RE and PMW contributed equally as senior authors.
1Brain
Tumour Research Program, 2Drug Discovery Unit, 3Phylogica Ltd, Telethon Kids Institute, University of Western Australia, Subiaco, Australia; 4Department of Paediatric Oncology and Haematology, Princess Margaret Hospital for Children, Roberts Road, Subiaco, Australia; 5School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia
SUMMARY Medulloblastoma, the most common pediatric malignant brain tumor, consists of at least four distinct molecular subgroups. Hyperactivation of the sonic hedgehog (SHH) pathway is a hallmark of SHH subgroup medulloblastoma, affecting approximately 30% of pediatric patients. While small molecules that inhibit Smoothened (SMO), a major driver of the SHH pathway, are efficacious for the treatment of SHH subgroup medulloblastoma, the development of drug resistance is a consistent problem, and SMO inhibitors are ineffective for those tumors driven by mutations affecting SHH pathway components downstream of SMO. In addition, the spectrum of mutations driving SHH subgroup medulloblastoma displays strong demographic variability, suggesting that a suite of SHH pathway inhibitors may be required to combat the heterogeneity of the disease in infants, children and adults. These issues have provided a major impetus for the development of novel and more effective SHH therapeutics. Peptide-based drugs have received little attention in the context of the SHH pathway, despite having potentially sig-
CONTENTS Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Medulloblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 The sonic hedgehog pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Sonic hedgehog subgroup medulloblastoma . . . . . . . . . . . . . . . . 120 Sonic hedgehog pathway inhibitors . . . . . . . . . . . . . . . . . . . . . . . . 120 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Medulloblastoma is the most common malignant brain tumor of childhood, and is one of the most significant causes of pediatric disease associated mortality in the developed world. Despite this grim statistic, there is currently unheralded optimism in the global medulloblastoma community. The prognosis for patients has improved gradually from < 50% 5-year survival 50 years ago (1), to average survival rates approaching 80% in 2014, and most encouragingly, a comprehensive molecular framework has recently been established that has facilitated a better understanding of the clinical and molecular heterogeneity of the disease (2). This molecular framework, which was developed through an unprecedented global collaborative research effort, has defined at least four molecular subgroups of medulloblastoma, and has galvanized drug discovery initiatives by providing a platform for the development of molecularly targeted therapies tailored to individual patients. MEDULLOBLASTOMA The molecular classification of medulloblastoma into four subgroups —Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4 (3-6)— correlates well with demographic (infant/child/adult) and clinical characteristics (Table I). Notably, WNT tumors (~10% cases) are rarely found in infants and have the most favorable prognosis (~90% 5-year survival), SHH tumors (~30% cases) have a bimodal distribution occurring more frequently in infants and adults and are associated with intermediate progno117
Drugs of the Future 2015, 40(2): 117-126
Copyright © 2015 Prous Science, S.A.U. or its licensors. All rights reserved. CCC: 0377-8282/2015 DOI: 10.1358/dof.2015.40.2.2262594

nificant advantages over small-molecule inhibitors. In particular, peptides can bind a larger and broader range of protein interfaces increasing the number of potential targets, in turn reducing the likelihood of drug resistance. Importantly also, peptides can be easily engineered for extended half-life, cell specificity and intracellular targeting. These advantages are discussed in the context of the variety of SHH pathway inhibitors that have been described so far, and the characteristics of critical components of the pathway that represent valid clinical targets. Key words: Medulloblastoma – Sonic hedgehog – Smoothened – Peptide inhibitors INTRODUCTION