Tissues Harvested Using an Automated Surgical Approach Confirm Molecular Heterogeneity of Glioblastoma and Enhance Specimen's Translational Research Value

Zusman, Edie E.; Sidorov, Maxim; Ayala, Alexandria; Chang, Jimmin; Singer, Eric A.; Chen, Michelle; Desprez, Pierre-Yves; McAllister, Sean D.; Salomonis, Nathan; Chetal, Kashish; Prasad, Gautam; Kang, Tyler Y.; Mark, Joseph; Dickinson, Lawrence; Soroceanu, Liliana

doi:10.3389/fonc.2019.01119

Cited by 9 publications

(3 citation statements)

References 31 publications

(39 reference statements)

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“…However, almost always a specimen that has been selected by the operating surgeon is available for research purposes ( Figures 2C–E ). During tumor resection, we use various surgical instruments, such as the NICO myriad device, to non-thermally mechanically dissociate the tissue ( 28 ) ( Figure 2D ). This tissue is then stored in a sterile container that is on ice.…”

Section: Intraoperative Considerationsmentioning

confidence: 99%

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

et al. 2021

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Neuro-oncology biobanks are critical for the implementation of a precision medicine program. In this perspective, we review our first year experience of a brain tumor biobank with integrated next generation sequencing. From our experience, we describe the critical role of the neurosurgeon in diagnosis, research, and precision medicine efforts. In the first year of implementation of the biobank, 117 patients (Female: 62; Male: 55) had 125 brain tumor surgeries. 75% of patients had tumors biobanked, and 16% were of minority race/ethnicity. Tumors biobanked were as follows: diffuse gliomas (45%), brain metastases (29%), meningioma (21%), and other (5%). Among biobanked patients, 100% also had next generation sequencing. Eleven patients qualified for targeted therapy based on identification of actionable gene mutations. One patient with a hereditary cancer predisposition syndrome was also identified. An iterative quality improvement process was implemented to streamline the workflow between the operating room, pathology, and the research laboratory. Dedicated tumor bank personnel in the department of neurosurgery greatly improved standard operating procedure. Intraoperative selection and processing of tumor tissue by the neurosurgeon was integral to increasing success with cell culture assays. Currently, our institutional protocol integrates standard histopathological diagnosis, next generation sequencing, and functional assays on surgical specimens to develop precision medicine protocols for our patients. This perspective reviews the critical role of neurosurgeons in brain tumor biobank implementation and success as well as future directions for enhancing precision medicine efforts.

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Section: Intraoperative Considerationsmentioning

confidence: 99%

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

et al. 2021

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“…Primary, patient-derived GBM cultures were generated in-house from tissue samples obtained during surgical resection of patients diagnosed with GBM. As previously described [78], tumors were subjected to enzymatic digest, mechanically dissociated and cultured as neurospheres. GBM neurospheres were expanded as intracranial xenografts (PDX) in athymic nu/nu mice and processed as previously described by [79].…”

Section: Methodsmentioning

confidence: 99%

Functional genomic analysis of adult and pediatric brain tumor isolates

Hoellerbauer

Biery

Arora

et al. 2023

Preprint

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Background: Adult and pediatric tumors display stark differences in their mutation spectra and chromosome alterations. Here, we attempted to identify common and unique gene dependencies and their associated biomarkers among adult and pediatric brain tumor isolates using functional genetic lethal screens and computational modeling. Methods: We performed CRISRP-Cas9 lethality screens in two adult glioblastoma (GBM) tumor isolates and five pediatric brain tumor isolates representing atypical teratoid rhabdoid tumors (ATRT), diffuse intrinsic pontine glioma, GBM, and medulloblastoma. We then integrated the screen results with machine learning-based gene-dependency models generated from data from >900 cancer cell lines. Results: We found that >50% of candidate dependencies of 280 identified were shared between adult GBM tumors and individual pediatric tumor isolates. 68% of screen hits were found as nodes in our network models, along with shared and tumor-specific predictors of gene dependencies. We investigated network predictors associated with ADAR, EFR3A, FGFR1 (pediatric-specific), and SMARCC2 (ATRT-specific) gene dependency among our tumor isolates. Conclusions: The results suggest that, despite harboring disparate genomic signatures, adult and pediatric tumor isolates share a preponderance of genetic dependences. Further, combining data from primary brain tumor lethality screens with large cancer cell line datasets produced valuable insights into biomarkers of gene dependency, even for rare cancers. Importance of the Study: Our results demonstrate that large cancer cell lines data sets can be computationally mined to identify known and novel gene dependency relationships in adult and pediatric human brain tumor isolates. Gene dependency networks and lethality screen results represent a key resource for neuro-oncology and cancer research communities.

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“…Cultures were generated in-house from tissue samples obtained during surgical resection of patients diagnosed with GBM. As previously described, 25 tumors were then subjected to enzymatic digest, mechanically dissociated and cultured as neurospheres as previously described. 26 Tumor lines were maintained as subcutaneous flank xenografts in athymic nu/nu mice and processed as stated above.…”

Section: Methodsmentioning

confidence: 99%

Cannabidiol inhibits RAD51 and sensitizes glioblastoma to temozolomide in multiple orthotopic tumor models

Soroceanu

Singer

Dighe

et al. 2022

Neuro-Oncology Advances

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Background Cannabidiol (CBD), a non-psychoactive cannabinoid with a low toxicity profile, has been shown to produce antitumor activity across cancers in part through selective production of reactive oxygen species (ROS) in tumor cells. The alkylating agent, temozolomide (TMZ), is standard of care for treatment of glioblastoma (GBM). It can trigger increased ROS to induce DNA damage. It has also been reported that down-regulating the expression of RAD51, an important DNA damage repair protein, leads to sensitization of glioblastoma to TMZ. Methods We determined the extent to which CBD enhanced the antitumor activity of TMZ in multiple orthotopic models of glioblastoma. In addition, we investigated the potential for CBD to enhance the antitumor activity of TMZ through production of ROS and modulation of DNA repair pathways. Results CBD enhanced the activity of TMZ in U87 MG and U251 GBM cell lines and in patient-derived primary GBM163 cells leading to stimulation of ROS, activation of the ROS sensor AMPK, and upregulation of the autophagy marker LC3A. CBD produced a sensitization of U87 and GBM163-derived intracranial (i.c.) tumors to TMZ and significantly increased survival of tumor-bearing mice. However, these effects were not observed in orthotopic models derived from GBM with intact methylguanine methyltransferase (MGMT) expression. We further demonstrate that CBD inhibited RAD51 expression in MGMT-methylated models of GBM, providing a potential mechanism for tumor sensitization to TMZ by CBD. Conclusion These data support the potential therapeutic benefits of using CBD to enhance the antitumor activity of TMZ in GBM patients.

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Tissues Harvested Using an Automated Surgical Approach Confirm Molecular Heterogeneity of Glioblastoma and Enhance Specimen's Translational Research Value

Cited by 9 publications

References 31 publications

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

Functional genomic analysis of adult and pediatric brain tumor isolates

Cannabidiol inhibits RAD51 and sensitizes glioblastoma to temozolomide in multiple orthotopic tumor models

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