Abstract 4671: Identification of novel drugs for glioblastoma using chemical biology fingerprinting

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Glioblastoma Multiforme (GBM) is an aggressive brain tumor with very poor prognosis and extremely limited therapeutic options. GBM is the most common malignant brain tumor and the search for novel targets and/ or the repurposing of already extant drugs to treat the disease is therefore of utmost importance. We describe here a comprehensive multidisciplinary approach to identifying said targets and ergo potential therapies. We have applied a novel analytical strategy to The Cancer Genome Atlas (TCGA) GBM expression data to stratify GBM into novel subtypes we call molecular contexts, or mCs. Subsequently, a panel of patient-derived GBM xenografts was ascribed to our novel mCs. Utilizing a technique we term Chemical Biology Fingerprinting, or CBF, short-term cultures derived from these clinically-relevant preclinical models were screened for chemosensitivity with a deeply annotated, yet clinically relevant, chemical library. Agents that were statistically more toxic to one context than another were then re-tested in true drug dose response experiments to confirm sensitivity. Preliminary data demonstrated that mC14, characterized by mutant p53 and transcriptionally similar to the GBM proneural subtype, showed distinct vulnerability to Arsenic Trioxide (ATO) as compared to mC4, enriched for NF1 mutations and with transcriptional patterns similar to the GBM mesenchymal subtype. To validate the ATO vulnerability signature in GBM, we acquired 20 treatment naive archival patient samples, that were part of a Phase I/II clinical trial to study the efficacy of ATO and Temozolomide in combination with ionizing radiation ([NCT00275067][1]). Participants in the trial exhibited varied survival with ATO treatment (91 days to >1000 days) and the clinical samples were subtyped into our molecular contexts using RNAseq data. In summary, we demonstrate a subclassification of GBM into novel molecular contexts (mCs) and show that these contexts are differentially sensitive to clinically relevant drugs. Citation Format: Darren Finlay, Harshil Dhruv, Lisa Evers, Sen Peng, Jeff Kiefer, Seungchan Kim, Jeffrey Raizer, Michael Berens, Kristiina Vuori. Identification of novel drugs for glioblastoma using chemical biology fingerprinting. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4671. doi:10.1158/1538-7445.AM2015-4671 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00275067&atom=%2Fcanres%2F75%2F15_Supplement%2F4671.atom