EXTH-06. INTEGRATED MOLECULAR PROFILING REVEALS TARGETABLE MOLECULAR ABNORMALITIES SHARED ACROSS MULTIPLE HISTOLOGIES OF BRAIN METASTASIS. (9th November 2020)

• Record Type: Journal Article
• Authors: Fukumura, Kazutaka; Malgulwar, Prit Benny; Fischer, Grant; Hu, Xiao Ding; Debeb, Bisrat Godefay; Yu, Dihua; Davies, Michael; Huse, Jason
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 2
• Page Start: ii87
• Page End: ii88
• Publication Date: 2020-11-09
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa215.360
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Brain metastases (BMs) occur in approximately 20–40% of patients with advanced cancer, and the estimated prevalence of new BMs in United States is between 200, 000–300, 000 per year. While the incidence of BM has increased over the past decades due to improvements in brain tumor detection technology, the prognosis is still very poor with the median overall survival times from weeks to few months. Therefore, identification of the precise molecular landscape and therapeutic targets for BMs is absolutely essential in tangible improvement of patient management. Here, we performed integrated genomic, transcriptional, and proteomic profiling in a cohort of lung, breast, and renal cell carcinomas consisting of both BMs and patient-matched primary or extracranial metastatic tissues to identify shared cellular and molecular factors driving BMs across distinct primary tumor histologies. Although the comprehensive analysis identified the unique genomic, transcriptional and proteomic landscapes according to the different histopathologies, elevated PI3K/AKT and RAS/MAPK signaling was observed as a generalizable feature across the entire specimen cohort, along with relative immunosuppression and metabolic upregulation of the electron transport chain (ETC). Interestingly, immunosuppression via T cell depletion was significantly associated with unfavorable prognosis of patients with BMs, and ETC inhibition as the prospective therapeutic target for BM patients was demonstrated using in vitro and in vivo disease models. Taken together, our findings suggest that abnormalities involving oncogenic signaling, metabolism, and the immune microenvironment are shared across multiple histologies of BMs, and may be amenable to therapeutic targeting.