Medulloblastoma drugs in development: Current leads, trials and drawbacks

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment for MB includes surgical resection, radiotherapy and chemotherapy. Despite significant progress in its management, a portion of children relapse and tumor recurrence carries a poor prognosis. Based on their molecular and clinical characteristics, MB patients are clinically classified into four groups: Wnt, Hh, Group 3, and Group 4. With our increased understanding of relevant molecular pathways disrupted in MB, the development of targeted therapies for MB has also increased. Targeted drugs have shown unique privileges over traditional cytotoxic therapies in balancing efficacy and toxicity, with many of them approved and widely used clinically. The aim of this review is to present the recent progress on targeted chemotherapies for the treatment of all classes of MB.

Keywords: Chemotherapy; Hh pathway; Medulloblastoma; Molecular targeting drugs; Wnt pathway.

Figure 1.. Illustration of proposed MB related proteins/pathways described in this review. (i) Conventional MB-related signaling pathways.

Components of canonical Wnt signaling pathway: FZD (frizzled), transmembrane receptor for Wnt ligand; DSH (dishevelled), transduces the Wnt signal to the cytoplasm; APC (adenomatosis polyposis coli), promotes the degradation of β-catenin; GSK3β (glycogen synthase kinase 3β), constitutively active protein kinase targeting β-catenin for degradation; Axin, component of β-catenin destruction complex; β-catenin, key mediator of canonical Wnt-signaling pathway. Components of canonical Hh-signaling pathway: Ptch (patched), transmembrane receptor for Hh ligands; Smo (smoothened), transmembrane receptor associated with Ptch and transducing Hh signal; Sufu (suppressor of fused homologue), negative regulator of Hh signaling; Gli (glioma-associated oncogene homologue), key transcription factor downstream of Hh signaling; Gli^A, active form of Gli that binds to DNA and serves as a transcriptional activator. (ii) Emerging proteins/pathways. Components of Sema3-Nrp signaling: Sema3 (Semaphorin 3), a member of a secreted ligand family; Nrps (neuropilins), transmembrane receptors for Sema3; PDE4D (phosphodiesterase 4D), translocating to cell membrane when recruited by Nrps; PKA (protein kinase A), cross-talk with Hh signaling through Gli. LSD1 (lysine demethylase 1), physically interacting with methylated lysines and Gfi1. HDAC (histone deacetylase) and BET (bromodomain and extraterminal domain), physically interacting with acetylated lysines. FACT (facilitates chromatin transcription), a histone chaperone to promote H2A/H2B dimer dissociation from the nucleosome and allow RNA polymerase II transcription on chromatin. PI3K (phosphoinositide 3-kinase), controlling Akt phosphorylation and activation status; Akt (protein kinase B), controlling mTOR phosphorylation and activation status; mTOR (mammalian target of rapamycin), key regulator downstream of PI3K-signaling. CDK (cyclin-dependent kinase), controlling the phosphorylation status of retinoblastoma. CK2 (casein kinase 2), involving p53 and MAPK phosphorylation status. Chk1 (checkpoint kinase 1), controlling Cdc25A phosphorylation status. ROCK (Rho-associated protein kinase), key regulator of Rho/ROCK-signaling, controlling MYPT1, MLC and LIMK1/2 phosphorylation status. Wee1, controlling Chk1/2 phosphorylation status. Src, controlling a wide range of protein phosphorylation, including PI3K. DDX3, a member of RNA helicase. PARP (poly(ADP-ribose) polymerase), interacting with single and double-strand DNA breaks. Sp1 (specific protein 1 transcription factor), binding to GC-boxes, CACCC-boxes and basic transcription elements. HMGCR (β-hydroxy β-methylglutaryl-CoA reductase), a key component of the mevalonate pathway that envolving a number of essential cellular functions. ABC (ATP-binding cassette) transporter, responsible for the translocation of multiple substrates across membranes. COX-2 (cyclooxygenases 2), envolves in tumor cells apoptosis and cell growth. DNA polymerases, catalyzes the synthesis of DNA molecules from nucleoside triphosphates. PP2A (protein phosphatase 2A), a serine/threonine phosphatase enhances anticancer immunity. mGPD (mitochondrial glycerophosphate dehydrogenase), a component of the glycerophosphate shuttle.