The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

Abstract

Introduction: Medulloblastoma (MB) is a heterogeneous tumor of the cerebellum that is divided into four main subgroups with distinct molecular and clinical features. Sonic Hedgehog MB (SHH-MB) is the most genetically understood and occurs predominantly in childhood. Current therapies consist of aggressive and non-targeted multimodal approaches that are often ineffective and cause long-term complications. These problems intensify the need to develop molecularly targeted therapies to improve outcome and reduce treatment-related morbidities. In this scenario, Hedgehog (HH) signaling, a developmental pathway whose deregulation is involved in the pathogenesis of several malignancies, has emerged as an attractive druggable pathway for SHH-MB therapy. Areas covered: This review provides an overview of the advancements in the HH antagonist research field. We place an emphasis on Smoothened (SMO) and glioma-associated oncogene homolog (GLI) inhibitors and immunotherapy approaches that are validated in preclinical SHH-MB models and that have therapeutic potential for MB patients. Literature from Pubmed and data reported on ClinicalTrial. gov up to August 2020 were considered. Expert opinion: Extensive-omics analysis has enhanced our knowledge and has transformed the way that MB is studied and managed. The clinical use of SMO antagonists has yet to be determined, however, future GLI inhibitors and multitargeting approaches are promising.

Drug Delivery Systems for Hedgehog Inhibitors in the Treatment of SHH-Medulloblastoma

“…Mutations and copy-number variation in critical genes of HH signaling (i.e., PTCH , SMO , SUFU , and GLIs ) cause an aberrant activation of this pathway and lead to formation of a wide spectrum of tumors ( Skoda et al, 2018 ). Therefore, pharmacological blockade of HH signaling has emerged as a promising anticancer therapeutic approach and a number of HH inhibitors have been designed and developed ( Lospinoso Severini et al, 2020 ). Most HH inhibitors affect the function of the SMO receptor even if their use for SHH-MB has shown several limits, especially due to SMO drug-resistance mutations ( Wang et al, 2013 ; Atwood et al, 2015 ; Danial et al, 2016 ).…”

“…Significant progress has been made in the identification and synthesis of a broad class of SMO antagonists. Two of them, vismodegib (GDC-0449) and sonidegib (LDE225), have been approved by the Food and Drug Administration (FDA) for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) and have entered in clinical trials for SHH-MB ( Dlugosz et al, 2012 ; Pak and Segal, 2016 ; Rimkus et al, 2016 ; Casey et al, 2017 ; Lospinoso Severini et al, 2020 ). However, different toxicity profiles and SMO drug-resistance mutations have limited their advanced clinical investigation ( Li et al, 2019 ).…”

“…However, different toxicity profiles and SMO drug-resistance mutations have limited their advanced clinical investigation ( Li et al, 2019 ). The major pitfalls of SMO inhibitors include both limited bioavailability and pharmacokinetics, due to unfavorable solubility, and low BBB permeability, thus restricting their use for central nervous system (CNS) tumors ( Li et al, 2019 ; Lospinoso Severini et al, 2020 ; Dias et al, 2021 ). In this scenario, nanoparticle-based drug delivery systems represent a valid opportunity to overcome these issues, by improving the pharmacological properties and safety profile of SMO antagonists, as well as their delivery across BBB ( Wei et al, 2014 ).…”

Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors

“…Therefore, combining our interest in natural products, cancer stem cells targeting [20,27] and Hh signalling inhibition, [23,28–37] here we propose the rational design and synthesis of a new class of potential withanolides‐inspired Smo inhibitors.…”

Specific Protein 1 and p53 Interplay Modulates the Expression of the KCTD-Containing Cullin3 Adaptor Suppressor of Hedgehog 2

“…Furthermore, a growing body of evidences suggests the involvement of Hh in a wider variety of cancers including prostate, gastric, breast, colon, and thyroid cancers (Teglund and Toftgård, 2010;Bushman, 2016;Wu et al, 2017;Xu et al, 2017;Riobo-Del Galdo et al, 2019;Xu et al, 2019), and in cancer cell stemness and multidrug resistance (Sari et al, 2018). Different therapeutic approaches to modulate the Hh pathway have been proposed (Rubin and de Sauvage, 2006;Lospinoso Severini et al, 2020), but the insurgence of mutations that confer tumor resistance is still a critical point, highlighting the need for a multitarget approach, acting on the Hh pathway at different levels (Rubin and de Sauvage, 2006;Lospinoso Severini et al, 2020;Quaglio et al, 2020).…”