Genomic and Protein Expression Profiling Identifies CDK6 As Novel Independent Prognostic Marker in Medulloblastoma

Meyer, Frank; Radlwimmer, Bernhard; Joos, Stefan; Kokocinski, Felix; Benner, Axel; Stange, Daniel E.; Neben, Kai; Fiegler, Heike; Carter, Nigel P.; Reifenberger, Guido; Korshunov, Andrey; Lichter, Peter

doi:10.1200/jco.2005.02.8589

Cited by 200 publications

(185 citation statements)

References 56 publications

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“…PPM1D (also known as PP2Cd and WIP1) is a member of the PPM family (Fiscella et al, 1997), which is characterized by Mg 2 þ /Mn 2 þ -dependent activity and relative insensitivity to okadaic acid. PPM1D is encoded by a putative oncogene that is amplified in multiple cancer types Li et al, 2002;Hirasawa et al, 2003;Saito-Ohara et al, 2003;Mendrzyk et al, 2005;Shreeram et al, 2006), including 11-16% of human primary breast cancers, most of which express wild-type P53 Li et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

et al. 2007

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The PPM1D gene is aberrantly amplified in a range of common cancers and encodes a protein phosphatase that is a potential therapeutic target. However, the issue of whether inhibition of PPM1D in human tumour cells that overexpress this protein compromises their viability has not yet been fully addressed. We show here, using an RNA interference (RNAi) approach, that inhibition of PPM1D can indeed reduce the viability of human tumour cells and that this effect is selective; tumour cell lines that overexpress PPM1D are sensitive to PPM1D inhibition whereas cell lines with normal levels are not. Loss of viability associated with PPM1D RNAi in human tumour cells occurs via the activation of the kinase P38. To identify chemical inhibitors of PPM1D, a high-throughput screening of a library of small molecules was performed. This strategy successfully identified a compound that selectively reduces viability of human tumour cell lines that overexpress PPM1D. As expected of a specific inhibitor, the toxicity to PPM1D overexpressing cell lines after inhibitor treatment is P38 dependent. These results further validate PPM1D as a therapeutic target and identify a proof-of-principle small molecule inhibitor.

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Section: Introductionmentioning

confidence: 99%

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

et al. 2007

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“…26,27 MiR-124 is the most abundant neuronal miRNA, playing a critical role in neurogenesis and neuronal differentiation. [28][29][30] Expression of miR-124a was shown to be significantly reduced in medulloblastomas compared to normal controls in this study, a trend similar to that observed in adult brain tumors.…”

Section: Mirnas In Medulloblastomamentioning

confidence: 99%

Normal and oncogenic roles for microRNAs in the developing brain

Fernández-L¹,

Northcott²,

Taylor³

et al. 2009

Cell Cycle

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M icroRNAS (miRNAs) are smallendogenous non-coding RNAs that play important roles in many different biological processes including proliferation, differentiation and apoptosis through silencing of target genes. Emerging evidence indicates that miRNAs are key players in mammalian development that, when altered, contribute to tumorigenesis. However, only a few studies to date have focused on the role of miRNAs in medulloblastoma, the most common malignant pediatric brain tumor. These tumors arise in the cerebellum and may attribute their origins to deregulated proliferation of neural progenitor cells during development. Understanding the interplay between normal brain development and medulloblastoma pathogenesis is necessary in order for more efficient, less toxic targeted therapies to be developed and implemented. MiRNA expression profiling of both mouse and human medulloblastomas has led to the identification of signatures correlating with the molecular subgroups of medulloblastoma, tumor diagnosis and response to treatment, as well as novel targets of potential clinical relevance. This review summarizes the recent miRNA literature in both medulloblastoma and normal brain development.

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“…[35][36][37] CDK6 is overexpressed in lymphoma, leukemia, glioma, glioblastoma, medulloblastoma, and cancers of squamous cells, salivary gland, bladder, pancreas and prostate. [38][39][40][41][42][43][44][45][46][47][48][49][50] In human prostate cancer cells, CDK6 has also been shown to bind androgen receptor and stimulate its activity in a kinase activity independent manner. 46 Blockage of CDK6 expression by microRNAs (miRNAs) has been shown to inhibit the proliferation of gliomas, medulloblastoma, prostate, bladder, gastric, hepatocellular, and lung cancer cells, indicating the significant role of CDK6 in the initiation and progression of these cancers.…”

Section: Introductionmentioning

confidence: 99%

“…48,54,71 Medulloblastoma comprises multiple and distinct molecular entities whose clinical and genetic differences likely require separate therapeutic strategies. Four principal sub-groups of medulloblastoma have been identified: those with Wnt pathway mutations, Sonic Hedgehog pathway mutations, and those termed Groups 3 and 4.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Genomic and Protein Expression Profiling Identifies CDK6 As Novel Independent Prognostic Marker in Medulloblastoma

Cited by 200 publications

References 56 publications

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D

Normal and oncogenic roles for microRNAs in the developing brain

Targeting CDK6 in cancer: State of the art and new insights

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