TMOD-03. GLIOMAPDOX: A MOLECULARLY DIVERSE LIBRARY OF DIRECT-FROM-PATIENT ORTHOTOPIC GLIOMA XENOGRAFTS RECAPITULATES INTRATUMOR HETEROGENEITY

The development of effective treatments for malignant brain tumors has been hampered by the lack of robust preclinical models that faithfully capture the high inter- and intra-tumor heterogeneity of the human disease. Conventional cell lines lose the most common genetic abnormalities of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology and drug efficacy. These systems are also under strong selection pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells and an overall shift away from in vivo characteristics. Here we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) that preserve the diverse genetic and transcriptional landscapes found in human GBMs. A paired comparison between matched patients, GliomaPDOX, and short-term primary cell cultures revealed transcriptional changes associated with altered nutrient availability and non-tumor cell interactions, emphasizing the impact of the tumor microenvironment on in vivo gene expression. Further, GliomaPDOX models preserved signatures of differentiated brain cell types recapitulating the intratumor heterogeneity of non-stem and stem-like cells found in patient tumors. These results are in contrast to those found in gliomapshere culture systems, where signatures of differentiated brain cells are abolished. Collectively these data show that GliomaPDOX is a model system that preserves defining molecular and anatomical characteristics of GBM and is well-suited for translational research investigations.