Abstract
BackgroundDespite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM).ResultsThe PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR). In vitro studies showed that volasertib inhibited cell viability, and high levels of the anti-apoptotic protein Bcl-xL expression were highly correlated with volasertib resistance. Volasertib sensitized GSCs to radiation therapy by enhancing G2/M arrest and by inducing apoptosis. Colony-formation assay demonstrated that volasertib plus IR synergistically inhibited colony formation. In intracranial xenograft mouse models, the combination of volasertib and radiation significantly inhibited GSC tumor growth and prolonged median survival compared with radiation treatment alone due to inhibition of cell proliferation, enhancement of DNA damage, and induction of apoptosis.ConclusionsOur results reinforce the potential therapeutic efficacy of volasertib in combination with radiation for the treatment of GBM.MethodsWe used high-throughput screening (HTS) to identify drugs, out of 357 compounds in the published Protein Kinase Inhibitor Set, with the greatest efficacy against a panel of glioma stem cells (GSCs), which are representative of the classic cancer genome atlas (TCGA) molecular subtypes.
Highlights
Glioblastoma (GBM) is the most common and aggressive form of primary brain tumors in adults
The Protein Kinase Inhibitor Set (PKIS) of 357 compounds was initially evaluated in 15 different glioma stem cells (GSCs) lines which led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using high-throughput screening (HTS) screening for cell viability
We further validated the HTS result with the second-generation polo-like kinase-1 (PLK1) inhibitor volasertib as a single agent and in combination with ionizing radiation (IR)
Summary
Glioblastoma (GBM) is the most common and aggressive form of primary brain tumors in adults. HTS was used to identify drug sensitivities to 357 compounds in the published Protein Kinase Inhibitor Set (PKIS) from GlaxoSmithKline (GSK) using a panel of GSCs, which are representative of the classic cancer genome atlas (TCGA) molecular subtypes [8] and are highly characteristic of human glioma growth patterns that contribute to tumor initiation and therapeutic resistance. From the initial 357 compounds, the 21 most highly active compounds were more extensively studied This HTS screen identified sensitivity of GSCs to inhibitors of polo-like kinase-1 (PLK1), a key regulator of mitosis [9]. We describe, for the first time, the in vitro and in vivo efficacy of volasertib as a single agent and combined with radiation in GSCs. Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM)
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