TMOD-02. PEDIATRIC MEDULLOBLASTOMA XENOGRAFT GROWTH LOCATION TRANSFORMS TRANSCRIPTOMIC BUT NOT PHENOTYPIC PROFILES AND ALTERS SENSITIVITY TO RADIATION. (31st May 2017)

• Record Type: Journal Article
• Authors: Etminan, Tina; Nan, Li; Moore, Blake; Orr, Brent; Hjelmeland, Anita; Ring, Eric; Beierle, Elizabeth; Markert, James; Chewning, Joseph; Crossman, David; Gillespie, Yancey; Friedman, Gregory
• Is Part Of: Neuro-oncology. Volume 19(2017)Supplement 4
• Page Start: iv48
• Page End: iv49
• Publication Date: 2017-05-31
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nox083.202
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Patient-derived xenograft models maintained in immunodeficient mice provide a powerful preclinical tool for testing oncologic therapies. Xenograft response to treatment informs which agents advance to human clinical trials. Frequently, pediatric brain tumor models are grown and tested heterotopically in the flank. We sought to determine if growing a Group 3 medulloblastoma xenograft in the flank compared to the brain altered the tumor profile. D341 Flank tumors were harvested and tumor pieces were injected into the flank or dissociated and 5x10 5 cells injected into the cerebrum. After tumor regrowth, tumors were harvested, prepared for routine histological examination, and duplicate biological samples were prepared for mRNA-sequencing (Illumina HiSeq2500). TopHat and Cufflinks were used to determine gene differences between each location (fold change ≥ ±2 and q-value <0.05). To compare location sensitivity to radiation, 10–20 mice were inoculated with 4x10 6 or 5x10 5 bioluminescently-enabled D341cells in the flank or cerebrum, respectively. Half of each group received 2 Gy of radiation 3 days/week for 6 doses. Bioluminescence was measured twice weekly. Tumor growth in the brain versus flank resulted in 348 significant gene differences. 90% of differences involved gene upregulation in the brain despite tumors appearing histologically similar. When normalized relative to their respective controls, mice lived 1.5x longer after tumor radiation in the flank compared to the brain. Average time for bioluminescence to recover back to baseline level after radiation was significantly greater (p<0.0001) in the flank (54.2 ± 10.7 days) versus brain (10.0 ± 2.1). Once tumors recovered from radiation (returned to baseline), they grew significantly faster (p=0.0021) in brain (time to 10-fold increase in bioluminescence: flank, 21.6 ± 11.0 days; brain 6.5 ± 0.5). These results suggest that significant genetic changes occur when a medulloblastoma xenograft is implanted in the flank compared to the brain and treatment sensitivity is modified. Further analysis is required to identify drivers of these changes.