Authors:
Dallas PB, Milech N, Gottardo NG, Hopkins RM, Endersby R, Watt PM.
Authors notes:
Drugs Future. 2015;40(2):117-26.
Keywords:
Medulloblastoma, Peptide inhibitors, Smoothened, Sonic hedgehog, cisplatin, cyclopamine, cyclophosphamide, patidegib, peptide, Smoothened protein, cancer prognosis, cancer resistance cell specificity, drug protein binding, gene mutation, human, protein targeting
Abstract:
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 significant 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.