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Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

ABSTRACT: Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants.Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling.Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors.We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study.

SUBMITTER: Binder ZA

PROVIDER: S-EPMC4814135 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

Binder Zev A ZA Wilson Kelli M KM Salmasi Vafi V Orr Brent A BA Eberhart Charles G CG Siu I-Mei IM Lim Michael M Weingart Jon D JD Quinones-Hinojosa Alfredo A Bettegowda Chetan C Kassam Amin B AB Olivi Alessandro A Brem Henry H Riggins Gregory J GJ Gallia Gary L GL

PloS one 20160330 3

<h4>Objective</h4>Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of ...[more]

PMID: 27028405

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Project description:Median survival for patients with recurrent GBM is <6 months. Front-line systemic therapy is temozolomide but resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity is implicated in poor outcomes. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional DNA alkylating agent that accumulates in brain tumor tissue. In in vitro studies, VAL-083 demonstrated activity in pediatric and adult GBM cell lines, as well as GBM cancer stem cells. Notably, VAL-083 overcomes resistance to MGMT in vitro. Previous clinical studies suggest that VAL-083 has anti-tumor activity against a range of tumors, including GBM. In light of extensive safety data from clinical trials and promising efficacy in CNS tumors, we initiated a new clinical study to establish the maximum tolerated dose (MTD) and identify a dose and dosing regimen for future efficacy trials in GBM. Early in the development of VAL-083, a cumulative IV dose of 125 mg/m2 delivered in a 35 day cycle in combination with radiation was shown superior to radiation alone in brain cancer (Eagan, et al. 1979). In the present study, the cumulative dose in a 33 day cycle ranges from 9 mg/m2 (cohort 1) to 240 mg/m2 (cohort 7). Six dose cohorts have completed the trial with no drug-related serious adverse events: MTD was not yet reached. Enrollment for cohort 7 (33 day cumulative dose: 240 mg/m2) has been initiated and higher doses may be explored; the results will determine the design of the safety and efficacy registration trial. METHODS: Open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a 3 + 3 dose-escalation design. Patients receive VAL-083 IV on days 1, 2, and 3 of a 21 day cycle. GBM patients previously been treated with surgery and/or radiation, if appropriate, must have failed both bevacizumab and temozolomide, unless contraindicated. ClinicalTrials.gov Identifier NCT01478178.

Dataset Information

Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

Publications

Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines.

Similar Datasets

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