Medulloblastoma is the most common malignant brain tumor in children.1
Despite treatment with surgery, radiation, and chemo, a substantial number of patients die as a result of tumor progression,2
and treatment-associated toxicities severely impair quality of life for most long-term survivors.1
The long-term goal of targeted therapeutics is to reduce systemic toxicity and normal brain injury while still achieving durable tumor control or cure.
Overexpression of CDK6 is present in approximately one-third of medulloblastomas and is an independent poor prognostic marker for this disease.3
Development of therapeutic agents that target inhibition of CDK6 may be effective for the subset of CDK6-positive tumors. For example, PD 0332991 is a highly specific small molecule inhibitor of CDK6 and CDK4 and has antitumor activity in human tumor xenografts.4
However, tumors acquire resistance to small-molecule inhibitors such as imatinib through several mechanisms, such as primary and secondary mutations.5
RNA interference (RNAi) is a powerful cellular process initiated by short double-stranded RNAs resulting in sequence-specific posttranscriptional gene silencing. The goal of RNAi-based therapy is to mimic naturally occurring RNAi and target specific messenger (m)RNA sequences to induce selective gene silencing. The principal advantages of RNAi over small-molecule and protein therapeutics are (i) ability to inhibit all targets, including “undruggable” ones;6
(ii) increased potency; and (iii) high specificity.
Micro (mi)RNAs are a class of small noncoding RNAs that regulate diverse cellular processes through RNAi-based mechanisms. MiRNAs are transcribed as primary RNA transcripts, processed in the nucleus to smaller precursor hairpin structures, and then exported to the cytoplasm, where they are processed further by the dicer nuclease to become mature, functional miRNAs ~21 nucleotides in length. Mature miRNAs, the endogenous equivalent of short-interfering (si)RNAs, are then incorporated into the RNA-induced silencing complex, which facilitates their interaction with, and inhibition of, target mRNAs by translational repression or message cleavage.7
One of the best characterized miRNAs in the central nervous system is miR-124. Expression of miR-124 is upregulated during development of the rodent nervous system8,9
during neuronal differentiation of embryonic stem cells10
and of mouse and human embryonal carcinoma cells.11
Furthermore, neuronal differentiation is enhanced following ectopic expression of miR-124 in mouse neuroblastoma cells,12
mouse embryonal carcinoma cells,10
and mouse embryonic stem cells.10
We have previously shown that miR-124 promotes neuronal differentiation of postnatal neural stem cells and glioma stem cells.13
MiR-124 is also an important regulator of adult neurogenesis in the subventricular-zone stem cell niche.14
Studies have shown that miR-124 is downregulated15,16
and that CDK6 is overexpressed in medulloblastoma tumors.3
MiR-124 inhibits expression of CDK6 and prevents proliferation of glioblastoma13
and medulloblastoma cells in vitro.15,16
In this report, we show that miR-124 inhibits proliferation of medulloblastoma cells in vitro and that induced expression of miR-124 potently inhibits growth of medulloblastoma xenograft tumors in rodents.