MBRS-64. SURPRISING ROLE FOR WNT SIGNALING IN SONIC HEDGEHOG DRIVEN MEDULLOBLASTOMA. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Rodriguez-Blanco, Jezabel; Pednekar, Lina; Penas, Clara; Li, Bin; Martin, Vanesa; Long, Jun; Lee, Ethan; Weiss, William; Rodriguez, Carmen; Mehrdad, Nadji; Nguyen, Dao; Ayad, Nagi; Rai, Priyamvada; Capobianco, Anthony; Robbins, David
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i142
• Page End: i142
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.508
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: The classification of specific cancers into distinct subgroups, based on emerging genomic technologies, has ushered in a new era of targeted therapeutics and companion diagnostics. This promise, however, is inconsistent with a model in which the growth of solid tumors, and their resistance to various chemotherapeutics, is driven by a small number of tumor-propagating cells whose transcriptome is unlikely to be captured by these technologies. We isolated such tumor propagating cells from a mouse model for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma. Medulloblastoma sphere cultures were enriched for the medulloblastoma progenitor marker SOX2, resistant to SHH inhibitors, and formed tumors in vivo. Surprisingly, these cultures, and their ability to self-renew were WNT-dependent. We show that Trp53 loss in these sphere cultures activated canonical WNT signaling and a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup medulloblastoma in vivo, in an on-target manner, leading to increased survival. Our results suggest that the tumor propagating cells driving the growth of bulk SHH-dependent medulloblastoma are themselves WNT dependent. Further, these results suggest WNT pathway inhibition as a novel therapeutic strategy to treat TRP53 deficient SHH-subgroup medulloblastoma patients, for whom few therapeutic options exist.