Alpha Omega Alpha Honor Medical Society

An ultrastructural immunogold examination of cerebral vasculature extracellular matrix proteins in a rat model of blast-induced mild traumatic brain injury

Investigator: Pierce Janssen

Mentors: Gregory Elder, MD; Miguel Gama Sosa, PhD

Objective:
To provide a report of an extensively characterized glioblastoma (GBM) patient-derived xenograft (PDX) panel generated from surgically resected samples and utilized as a biologically relevant platform for brain tumor research.

Methods:
From 2000-2015, 208 surgical specimens were collected from patients with primary brain tumors, of which 77 (37% engraftment rate) tumors successfully engrafted and were serially passaged for a minimum of 3 generations in the subcutaneous flank of athymic mice. Orthotopic tumors were generated by stereotactic injection of short-term explant cultures generated from cryopreserved early-passage flank tumor tissue. Molecular comparison of patient and corresponding PDX tumors were performed using array comparative genomic hybridization (aCGH) and whole-exome sequencing (WES). Moreover, extensive molecular and phenotypical characterizations were performed across the entire Mayo PDX panel using aCGH, WES, RNA-sequencing, and tissue-microarray analyses.

Results:
Successfully engrafted samples were predominately from WHO Grade IV gliomas, yielding a 44% (77/174) engraftment rate for these tumors. Compared to newly diagnosed GBM patients, overall survival (OS) was significantly worse for patients with recurrent/secondary GBM tumors that were xenografted (p=0.002). Comparison of patient and corresponding PDX tumors using aCGH and WES data highlight a high degree of molecular and genomic fidelity associated with the xenografting process. Furthermore, molecular and phenotypic characterization for each PDX line revealed that these models encompass the breadth of molecular heterogeneity reported in GBM tumors, which will allow investigators the ability to select relevant tumor models to test specific molecular hypotheses.

Conclusions:
This study describes a large-scale molecular and phenotypic annotation of an orthotopic GBM PDX panel and provides supporting evidence that these models demonstrate high concordance with corresponding clinical specimens; thus, providing a translationally relevant platform to ultimately develop and investigate novel therapeutic agents against this uniformly deadly disease.

Last modified: 2/01/2017

Updated on February 3, 2017.


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