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• W1531852839 abstract "With the discovery of the preponderance of activating BRAF mutations in human melanoma, and the first successes in developing drugs to treat melanoma by specifically targeting the mutant BRAF protein, there is finally some optimism in the therapeutic arena. However, development of resistance to BRAF inhibitors remains a problem to be overcome and the search for additional compounds for the oncologist’s arsenal has not slowed. In this regard, a recent study headed up by Leonard Zon’s group at Children’s Hospital Boston (White et al., 2011) highlights the potential of starting from a relatively simple premise, taking an unbiased approach (in this case, gene expression profiling followed by a whole-organism small molecule screen) and then following its lead to unexpected places. In this case the multi-pronged approach began with a zebrafish model. Zon’s group was the first to demonstrate that the expression of the BRAF-V600E mutant can lead to melanocyte overgrowth and melanoma in zebrafish as it does in humans (Patton et al., 2005). White and colleagues wanted to know the relationship between the earliest cells expressing BRAF-V600E in the embryo, that is, neural crest cells, and the BRAF-V600E-expressing melanomas that arise in the adults. Microarray analysis was used to identify sets of genes enriched in BRAF-V600E-transgenic, p53-mutant (BRAF; p53) embryos over wild-type and single mutant/transgenic embryos, and in BRAF; p53 tumors over normal tissue. Comparing the enriched gene sets of melanomas and mutant embryos gave a 123 gene ‘overlap signature’. Notable for this signature were several markers of neural crest progenitors. This suggested that melanomas retain a neural crest-like character, and that the neural crest cells of mutant embryos may show defective differentiation. Similarly, human melanomas were found to express progenitor markers. One of the progenitor genes that was maintained in the zebrafish embryos and tumors was the zebrafish-specific pan-neural crest marker crestin. White et al. decided to use crestin expression as the basis of small molecule screen in zebrafish embryos, with the goal of finding compounds that suppressed the formation of neural crest progenitors. The great advantage of performing such a screen in a whole embryo is its built-in specificity: its potential to differentiate compounds that target one particular cell population rather than being generally toxic. One molecule that was highly effective, NCS210627 was found to be structurally related to brequinar, a known inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme in the pyrimidine biosynthetic pathway. Another known DHODH inhibitor, Leflunomide, was found to have similar effects and was used for the majority of the remaining studies. NCS21027 and Leflunomide effectively eliminate embryonic crestin expression, and also decrease pigmentation in treated zebrafish embryos, reduce expression from neural crest reporter transgenes (mitfa:GFP and myelin basic protein:mCherry), and produce defects in jaw development. Non-neural crest lineages were surprisingly far less affected. Nearly half of the 123 BRAF; p53 signature genes showed down-regulation upon DHODH inhibition, including the early neural crest markers. This observation led the investigators to examine if the drug may be affecting neural crest stem cells (NCSCs). In fact, isolated rat neural crest stem cells treated with DHODH inhibitor produced fewer and smaller colonies in a colony formation assay, with no effect on differentiation or survival, nor biased toward particular neural crest lineages. This suggests that DHODH inhibition specifically interferes with self-renewal of NCSCs. The morphological phenotype resulting from DHODH inhibition during embryogenesis was noted to be similar to that of zebrafish with mutations in genes encoding transcriptional elongation factors spt5 or spt6 (Keegan et al., 2002), and this similarity was borne out by comparison of drug treatment-versus-mutant gene expression profiles. Demonstration that spt5 heterozygous embryos, as well as a hypomorphic spt5 allele, are sensitized to low doses of Leflunomide relative to wild-type siblings indicated a genetic interaction between DHODH and spt5. Together these experiments suggested that Leflunomide works at the level of transcriptional elongation, which was further supported by quantitative RT-PCR comparison between 5′ and 3′ ends of target transcripts in cultured melanoma cells. However, the definitive test was chromatin immunoprecipitation-sequencing (ChIP-seq) with RNA polymerase II, showing greater occupancy by transcription complexes near promoters versus within the body of signature genes after drug treatment, with no effect on initiation. This genome-wide approach also identified among the genes enriched in the transcriptionally-stalled subset numerous targets of c-Myc, shown recently to be integral to regulated transcriptional pausing (Rahl et al., 2010). So what effect does a compound that blocks transcriptional elongation in neural crest progenitor cells have on melanoma? White and co-workers show that the Leflunomide derivative A771726 reduces the proliferation of melanoma cells in culture, a result also produced by shRNA versus DHODH itself. When combined, the BRAF inhibitor PLX4720 (Tsai et al., 2008) and A771726 showed a cooperative effect. A771726 has a weak effect on non-melanoma cell lines (that have wild-type BRAF) on which PLX4720 has no effect. Finally, the authors examine the effects of Leflunomide and the Leflunomide/PLX4720 combination in A375 melanoma cell xenografts into nude mice: while Leflunomide was as effective as PLX4720 on its own in suppressing tumor growth, the combination was yet more effective, with further reduced tumor growth and 40% of animals showing complete tumor regression. These intriguing findings of White and colleagues add to data highlighting the newfound importance of elongation factors in development and in cancer. This includes evidence that CHD7, the chromatin-remodeling factor associated with CHARGE syndrome (which has a significant neural crest component), acts as a global regulator of transcription by RNA pol II (Srinivasan et al., 2008). The reasons that the neural crest appears to be particularly sensitive to DHODH inhibition and dysregulation of elongation will be an interesting avenue of future investigation. The identification of a class of compounds including Leflunomide (a medication already approved to treat rheumatoid arthritis) as a potential therapy against melanoma shows that when properly designed and executed, small molecule screens can be ‘fishing expeditions’ of the successful variety." @default.
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• W1531852839 date "2011-03-30" @default.
• W1531852839 modified "2023-09-23" @default.
• W1531852839 title "Melanocytes and melanoma: hooked on elongation" @default.
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• W1531852839 doi "https://doi.org/10.1111/j.1755-148x.2011.00846.x" @default.
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