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

Han, Youjia; Lindner, Sven; Bei, Yi; García, Heathcliff Dorado; Timme, Natalie; Althoff, Kristina; Odersky, Andrea; Schramm, Alexander; Lissat, Andrej; Künkele, Annette; Deubzer, Hedwig E.; Eggert, Angelika; Schulte, Johannes H.; Henssen, Anton

doi:10.1016/j.canlet.2018.12.012

Cited by 22 publications

(19 citation statements)

References 61 publications

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“…Volasertib causes arrest in early M phase and results in a monopolar spindle, halting entry into prometaphase. Volasertib-induced cell-cycle arrest has been shown across several model systems [15, 38, 39] and is consistent in a representative hepatoblastoma cell culture (Figure 7A). SN38 inhibits topoisomerase I activity by binding TOP1 and DNA, preventing re-ligation of the DNA and causing arrest in S phase.…”

Section: Resultssupporting

confidence: 67%

Volasertib preclinical activity in high-risk hepatoblastoma

et al. 2019

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Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with in vitro activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both in vitro and in vivo efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.

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Section: Resultssupporting

confidence: 67%

Volasertib preclinical activity in high-risk hepatoblastoma

et al. 2019

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“…In addition, JQ1 decreases the acetylation level and activity of mutant p53, inducing cell growth arrest and subsequent senescence in HNSCC (202). OTX015 (MK-8628, birabresib), one of BRD and extra-terminal domain inhibitors, exhibits antitumor activity in medulloblastoma, B-cell lymphoma, and lung cancer (179,184,203). In addition, BET inhibitors such like PLX51107 and NHWD-870 have been identified the activity of tumor proliferation suppression (204,205).…”

Section: Brd Inhibitorsmentioning

confidence: 99%

Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

Qiu²,

Jiao

et al. 2020

Front. Oncol.

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Evidence for research over the past decade shows that epigenetic regulation mechanisms run through the development and prognosis of tumors. Therefore, small molecular compounds targeting epigenetic regulation have become a research hotspot in the development of cancer therapeutic drugs. According to the obvious abnormality of histone acetylation when tumors occur, it suggests that histone acetylation modification plays an important role in the process of tumorigenesis. Currently, as a new potential anti-cancer therapeutic drugs, many active small molecules that target histone acetylation regulatory enzymes or proteins such as histone deacetylases (HDACs), histone acetyltransferase (HATs) and bromodomains (BRDs) have been developed to restore abnormal histone acetylation levels to normal. In this review, we will focus on summarizing the changes of histone acetylation levels during tumorigenesis, as well as the possible pharmacological mechanisms of small molecules that target histone acetylation in cancer treatment.

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“…Whole-cell protein lysate preparation was performed with RIPA buffer (15 mM HEPES, 150 mM NaCl, 10 mM EGTA, 2% Triton X-100) supplemented with protease and phosphatase inhibitors (complete mini EDTA-free and PhosSTOP, Roche) as described before [14,21,35]. Bicinchoninic acid assay (Santa Cruz Biotechnology, Texas, USA) was used for protein quantitation according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Simultaneous inhibition of multiple therapeutic targets is an established strategy to improve the durability of clinical responses to targeted therapy. We and others have recently described that combined treatment with small molecule BRD4 and polo-like kinase 1 (PLK1) inhibitors has synergistic antitumor effects in medulloblastoma and acute lymphoid leukaemia [20,21]. PLK1 is overexpressed in pediatric solid tumors and high expression is associated with poor prognosis [[22], [23], [24]].…”

Section: Introductionmentioning

confidence: 99%

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

Timme

Han

Liu

et al. 2020

Translational Oncology

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

Cited by 22 publications

References 61 publications

Volasertib preclinical activity in high-risk hepatoblastoma

Volasertib preclinical activity in high-risk hepatoblastoma

Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

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

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