Publications by authors named "Natalie Timme"

4 Publications

  • Page 1 of 1

Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors.

Transl Oncol 2020 Feb 21;13(2):221-232. Epub 2019 Dec 21.

Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Experimental and Clinical Research Center (ECRC) of the Charité and the Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany; Deutsches Konsortium für Translationale Krebsforschung, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. Electronic address:

Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.
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http://dx.doi.org/10.1016/j.tranon.2019.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931204PMC
February 2020

Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma.

Nat Genet 2020 01 16;52(1):29-34. Epub 2019 Dec 16.

Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.
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http://dx.doi.org/10.1038/s41588-019-0547-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008131PMC
January 2020

Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma.

Cancer Lett 2019 03 4;445:24-33. Epub 2019 Jan 4.

Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany; German Consortium for Translational Cancer Research (DKTK), Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1.
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http://dx.doi.org/10.1016/j.canlet.2018.12.012DOI Listing
March 2019