Dichotomy in Growth and Invasion From Low to High Grade Glioma Cellular Variants

Abstract Glial dysfunction outraging CNS plasticity and integrity results into one of the most dangerous cancer, namely glioma, featuring little median survival period and high recurrence. The hallmark properties of proliferation, invasion and angiogenesis with the infiltrated macrophages in glioma are expected to be tightly coupled or cross-linked, but not definitely related so far. Present study is aimed to find a relationship between this featured quadrangle from lower to higher grades of post-operative glioma tissues and their invading subsets. Elevated Ki67 associated proliferation in lower grades was supported with VEGF dependent angiogenic maintenance which found decrease unlikely in higher grades. In contrast, MMP-2 and 9 associated invasions augmented high in higher grades with dominant presence of CD204+ M2 polarized macrophages and a general increase in global DNMT1 associated methylation. Marked differences found in ECM invading cellular subsets of higher grades showing high proliferative capacity indicating rationally for recurrence, contrasting the nature of gross tumor tissue of same grade. Thus in lower grades the neoplastic lesion is more inclined for its growth while in higher grade more disposed towards tissue wreckage in support with cellular environmental milieu whereas the cellular variants and subsets of invaded cells showed different trends. Therefore, some operational dichotomy or coupling among cellular variants in glioma is active in determining its low to high grade transition and aggressive progression.

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Pediatric high-grade glioma resources from the Children’s Brain Tumor Tissue Consortium

Neuro-Oncology ◽

10.1093/neuonc/noz192 ◽

2019 ◽

Vol 22 (1) ◽

pp. 163-165 ◽

Cited By ~ 4

Author(s):

Heba Ijaz ◽

Mateusz Koptyra ◽

Krutika S Gaonkar ◽

Jo Lynne Rokita ◽

Valerie P Baubet ◽

...

Keyword(s):

Brain Tumor ◽

Tumor Tissue ◽

High Grade Glioma ◽

High Grade ◽

Pediatric High Grade Glioma

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ATIM-21. INTRAVENOUS DELIVERY OF TOCA 511 IN PATIENTS WITH HIGH GRADE GLIOMA RESULTS IN QUANTIFIABLE EXPRESSION OF CYTOSINE DEAMINASE IN TUMOR TISSUE

Neuro-Oncology ◽

10.1093/neuonc/nox168.116 ◽

2017 ◽

Vol 19 (suppl_6) ◽

pp. vi30-vi31

Author(s):

Tobias Walbert ◽

Daniela Bota ◽

Michael Vogelbaum ◽

Steven Kalkanis ◽

Linda Liau ◽

...

Keyword(s):

Tumor Tissue ◽

Cytosine Deaminase ◽

High Grade Glioma ◽

High Grade

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HGG-40. HIGH GRADE GLIOMA CELL LINE COHORT AS AN EXAMPLE OF CHILDREN’S BRAIN TUMOR TISSUE CONSORTIUM TUMOR SPECIMEN PROCESSING PIPELINE

Neuro-Oncology ◽

10.1093/neuonc/noy059.312 ◽

2018 ◽

Vol 20 (suppl_2) ◽

pp. i97-i97

Author(s):

Mateusz Koptyra ◽

Valerie Baubet ◽

Lamiya Tauhid ◽

Namrata Choudhari ◽

Tiffany Smith ◽

...

Keyword(s):

Brain Tumor ◽

Cell Line ◽

Glioma Cell ◽

Tumor Tissue ◽

High Grade Glioma ◽

Glioma Cell Line ◽

High Grade ◽

Processing Pipeline ◽

Tumor Specimen ◽

Specimen Processing

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BIOM-56. THE INTEGRATION OF A LIQUID BIOPSY PROGRAM INTO THE CARE OF PEDIATRIC BRAIN TUMOR PATIENTS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.053 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii13-ii14

Author(s):

Alexandra Miller ◽

Luca Szalontay ◽

Hamza Ahmad ◽

Nancy Bouvier ◽

Irene Rodriguez-Sanchez ◽

...

Keyword(s):

Liquid Biopsy ◽

Tumor Tissue ◽

Clinical Care ◽

High Grade Glioma ◽

Response To Therapy ◽

Low Grade ◽

High Grade ◽

Cell Free Dna ◽

Free Dna ◽

Minimal Residual

Abstract Pediatric CNS tumors remain the leading cause of cancer-related death in children and adolescents. Safe sampling of tumor tissue for diagnostic purposes may be difficult if not impossible. Detection of minimal residual or recurrent disease prior to definitive clinical or radiographic progression may allow earlier initiation of novel therapies and ultimately improve overall survival. Given the rarity of serial sampling of tumor tissue, our understanding of molecular evolution in response to therapy remains limited. Recent technological advances have led to the development of “liquid biopsy” assays, which detect cell-free DNA (cfDNA) in blood, cerebrospinal fluid (CSF) or other bodily fluids. Here, we report our initial clinical experience with the recently established MSK Kids pediatric neuro-oncology liquid-biopsy program at Memorial Sloan Kettering Cancer Center (MSKCC) using MSK-IMPACT, which is clinically validated by the New York State Department of Health for CSF cell-free DNA (cfDNA)vprofiling. All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. Samples from 29 unique patients were sequenced. Histopathology included high-grade glioma (5); low-grade glioma (2); medulloblastoma (8); pineoblastoma (3); retinoblastoma (4); other (7). CSF cfDNA could be detected in 18/42 samples (43%) and 12/29 patients (34%). CSF cfDNA was more commonly detected in higher-grade, disseminated tumors such as high-grade glioma (60%), medulloblastoma (38%), and pineoblastoma (100%). Low-grade lesions without leptomeningeal involvement did not result in detectable CSF cfDNA shedding (86% were negative). In a subset of patients, MSK-IMPACT identified previously unrecognized molecular actionable targets (e.g. BRAF-KIAA1549 fusion); or the detection of “minimal residual disease” prior to the detection of tumor recurrence by conventional diagnostics, impacting clinical care decisions. Future directions include integration of CSF cfDNA into prospective clinical trials as a correlative biomarker.

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INNV-26. IN VITRO CHEMO RESISTANCE PROFILES OF CIRCULATING GLIAL CELLS REPLICATE CHEMO CHARACTERISTICS OF TUMOR TISSUE

Neuro-Oncology ◽

10.1093/neuonc/noz175.567 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi135-vi135

Author(s):

Dadasaheb Akolkar ◽

Sanket Patil ◽

Vishakha Mhase ◽

Pradip Devhare ◽

Pooja Fulmali ◽

...

Keyword(s):

Glial Cells ◽

Peripheral Blood ◽

Drug Response ◽

Tumor Tissue ◽

High Grade Glioma ◽

Cytotoxic Drugs ◽

High Grade ◽

Label Free ◽

Chemotherapy Drugs

Abstract Survival of high-grade glioma patients remains dismal due to onset of resistance to even the limited systemic treatment option currently available. Except for indirect prediction of alkylating agent Temozolomide response through MGMT promotor methylation and NTRK fusions for larotrectinib, there are no biomarkers available for drug response prediction. Cell based, in vitro chemosensitivity assays can interrogate the efficacy of an array of cytotoxic drugs. However, the unavailability of live tumor cells for such assays pose challenges in clinical practice. Repeat biopsies are neither advisable nor feasible. Access to Circulating Glial Cells (CGCs) can provide real time insight into the chemo dynamics of the tumor. In this study, we show for the first time that CGCs can be harvested from peripheral blood of glioma patients for chemo response and resistance profiles (CRR) of cytotoxic drugs. CGCs were harvested from 15 ml of peripheral blood from high grade GBM patients (n=9) out of whom cells derived from surgically excised tumor tissue were also available for comparison in 2 patients. CellWizard™ process was adopted for enrichment of CGCs which is based upon epigenetically active media with paradoxical chemo-toxicity that selectively induces lethality in normal cells. This paradoxical cytotoxicity of the medium leads to selective elimination of most leukocytes thus facilitating a label free negative enrichment of CGCs. In vitro chemo sensitivity assay performed on live CGCs and cell death events were determined to evaluate response to different class of chemotherapy drugs. Evaluation of drug response showed very high concordance between tumor derived cells and CGCs in both patients where live tissue was available. In 7 patients where CGCs alone could be evaluated, the response showed replication between in vitro profile compared to treatment antecedents in 5 patients. 2 patients were treatment naïve and the response reflected high sensitivity to Temozolomide.

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Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)

10.1101/656587 ◽

2019 ◽

Author(s):

Heba Ijaz ◽

Mateusz Koptyra ◽

Krutika S. Gaonkar ◽

Jo Lynne Rokita ◽

Valerie P. Baubet ◽

...

Keyword(s):

Brain Tumor ◽

Cell Lines ◽

Glioma Cell ◽

Tumor Tissue ◽

Pediatric Brain Tumor ◽

High Grade Glioma ◽

High Grade ◽

Primary Tumors ◽

Pediatric Brain ◽

Pediatric High Grade Glioma

ABSTRACTBackgroundPediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release (October 2018) of the Pediatric Brain Tumor Atlas (PBTA).MethodspHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created.ResultsThe pHGG set included 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAF V600E variants). A pHGG TMA (n=77), includes 36 (53%) patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency.ConclusionThe CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.IMPORTANCE OF STUDYHigh-grade gliomas (HGG) remain the leading cause of cancer death in children. Since molecularly heterogeneous, preclinical studies of pediatric HGG will be most informative if able to compare across groups. Given their relatively rarity, there are few readily available biospecimens and cellular models to inform preclinical laboratory and genomic translational research. Therefore, the aim of this CBTTC study was to highlight the panel of pediatric HGG cases whose primary tumors have undergone extensive genomic analysis, have clinical data, available imaging and additional biospecimens, including tumor, nucleic acids, cell lines and FFPE tissue on a tissue microarray (TMA).

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PDTM-16. PEDIATRIC HIGH GRADE GLIOMA RESOURCES FROM THE CHILDREN’S BRAIN TUMOR TISSUE CONSORTIUM (CBTTC) AND PEDIATRIC BRAIN TUMOR ATLAS (PBTA)

Neuro-Oncology ◽

10.1093/neuonc/noz175.792 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi190-vi190

Author(s):

Heba Ijaz ◽

Mateusz Koptyra ◽

Krutika Gaonkar ◽

Jo Lynne Rokita ◽

Valerie Baubet ◽

...

Keyword(s):

Brain Tumor ◽

Mismatch Repair ◽

Cell Lines ◽

Glioma Cell ◽

Tumor Tissue ◽

Pediatric Brain Tumor ◽

High Grade Glioma ◽

High Grade ◽

Pediatric Brain ◽

Pediatric High Grade Glioma

Abstract BACKGROUND Pediatric high grade glioma (pHGG) remains a fatal disease. Access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children’s Brain Tumor Tissue Consortium (CBTTC) from the first release of the Pediatric Brain Tumor Atlas (PBTA). METHODS pHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created. RESULTS The pHGG set includes 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Operative reports, pathology reports and histology images are available for nearly all cases. Pre- and post-operative MRI images and reports are also available for a subset. Tumor WGS/RNAseq is available for 70 subjects. Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAFV600E variants). In our panel of pHGG, six patients (8 tumors) harbored germline mismatch repair mutations with tumor hyper-mutation. A pHGG TMA (n=77), includes 36 patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency. CONCLUSION The CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.

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