Myc proteins in brain tumor development and maintenance 127 Targeting these transcription factors that lack clear binding domains have always proved difﬁcult, and using short interfering RNAs (like speciﬁc short hairpin RNAs) that target Myc directly is not yet a treatment option for patients. There are, however, small molec- ular drugs that inhibit Myc-Max interactions that are effective in cancers like human acute myeloid leukemia (120-122). Promoting Mad, another bHLH protein that antagonizes Myc, would be another promising approach in brain tumor therapy (123). There are other ways to induce growth arrest and senescence in childhood medulloblastoma and in atypical teratoid/rhabdoid tumor cells by using G-quadruplex interactive agents in order to disable c-myc at the promoter level (124). It is also possible to target regulatory components in which Myc controls ribosome biogenesis (125). Myc can regulate transcription of ribosomal proteins through RNA polymerase II (RNA pol II) (126,127). MYC parti- cipates in release of paused RNA pol II, as c-myc can bind positive elongation factor b (P-TEFb) and stimulate transcriptional elongation in cancer cells. Combined targeting of c-myc and P-TEFb could prove effective for tumors maintained by Myc proteins (128). Another strategy is to force changes in chromatin modiﬁcation controlled by Myc genes (129). For example, histone lysine side-chain acety- lation increased by c-myc can be effectively suppressed by inhibition of acetyl-lysine recognition domains (bromodomains) in multiple myeloma, a Myc-dependent hematologic cancer (130). Pathways downstream of receptor tyrosine kinases like MAPK/ERK and PI3K/Akt/mTOR that indi- rectly control Myc protein stability (Figure 1) are often overexpressed or altered in brain tumors. MAPK/ERK kinase inhibitors can dephosphorylate c-myc and reduce cell proliferation and anchorage- independent growth of rhabdomyosarcoma (131), a soft tissue sarcoma in children. However, down- stream of Shh signaling, Cdk1 rather than ERK is associated with S62 activity, at least in granule neuron precursors (69,70) that could serve as medulloblas- toma cells of origin (13,132). The cyclin-dependent kinase sibling Cdk2 can also phosphorylate S62. Yet, while Cdk2 inhibitors will promote senescence in Myc-induced cells (133), Cdk1 inhibitors (134) can be used to promote the apoptotic effects induced by Myc proteins (135). This is also the suggested cell death that temozolomide treatment promotes from c- myc via Akt signaling in O6-methylguanine-DNA methyl transferase (MGMT) expressing glioblastoma (136). Akt activity also determines the sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating c-myc expression (137). Moreover, mTOR exists in a complex, mTORC1, that directly phosphorylates and inhibits PP2A (138) which (as described above and visualized in Figure 1) will lead to sustained Myc protein activity. Consequently, clinical inhibitors of PI3K/mTOR prove efﬁcacy when used to degrade Mycn in neuroblastoma (139,140), a childhood tumor thought to originate from the peripheral neural crest. Such PI3K/mTOR inhibitors are indeed also effective in suppressing glioma (141) and medulloblastoma (142). Other examples to target Myc protein stability include treatment with clinically available synthetic steroid drugs, like dexamethasone, that can be used to destabilize Mycn, leading to inhibited growth of Shh-dependent medulloblastoma (143). Ultimately, drugs that can target regulators of the ubiquitin-proteasome system (reviewed in (144)) can promote ﬁnal degradation of long-lived and harmful Myc proteins also in brain tumor cells. To summarize, there are numerous observations about how Myc proteins co-ordinate cell transformation and many promising ideas on how to target these proteins in brain tumors, so let’s keep on hunting. Acknowledgements Research in the author’s laboratory has been supported by grants from The Swedish Childhood Cancer Foundation, The Swedish Cancer Society, The Pediatric Brain Tumor Foundation, The Swedish Research Council, Åke Wibergs stiftelse, Lions Cancerforskningsfond, and Stiftelsen Lars Hiertas Minne. Declaration of interest: The author reports no conﬂicts of interest. The author alone is responsible for the content and writing of the paper. References 1. Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev. 2008;22:2755–66. 2. Stanton BR, Perkins AS, Tessarollo L, Sassoon DA, Parada LF. Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop. Genes Dev. 1992;6:2235–47. 3. 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