Abstract 4366: ShRNA-based cellular proliferation signaling analysis revealed DRD2 as a novel therapeutic target for glioblastoma.

Abstract

Abstract Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within one year of diagnosis. Our best current understanding of its etiology is that glioblastoma involves genetic and epigenetic changes that subvert the inherent molecular circuitry of glial cells to drive uncontrolled cellular proliferation. Unfortunately, this molecular circuitry in glioblastoma appears sufficiently complex and redundant that disruption at any particular point tends to redirects signaling through the remaining circuit. In this context, meaningful therapeutic gains will require the identification of therapeutic agents that target critical nodes within this circuit. To identify novel therapeutic agents that target critical nodes which regulate cellular proliferation, a genome-wide retroviral shRNA library screen was conducted in two glioblastoma cell lines (U87MG and A172) and two lung carcinoma lines (A549 and NCI-H460). Pathway analysis of the pro-proliferative genes using both PANTHER and Ingenuity software revealed an over-representation of G-protein coupled neurotransmitter receptors (GPCR), including dopamine receptor subtype 2 (DRD2), which was also highly expressed in glioblastoma specimens relative to the matched normal parentchymal. Further investigation demonstrated that DRD2 signal regulates cell growth by GNAI2-induced ERK activation. Moreover, Haloperidol, one of DRD2 antagonists, enhances significantly anti-tumor efficacy of EGFR inhibitor AG1478 using U87 and mesenchymal neuroshpere xenografy mouse models. Given that both AG1478 and DRD2 antagonists have been approved for the treatment of glioblastoma and psychotics, separtately, Haloperidol combined with chemotherapy represents a novel and likely conducted strategy for the treatment of glioblastoma. Citation Format: Jie Li, Shan Zhu, David Kozono, Diahnn Futulan, David Gonda, Deepa Kushwaha, Kristopher Kahle, Stephen Elledge, Clark C. Chen. ShRNA-based cellular proliferation signaling analysis revealed DRD2 as a novel therapeutic target for glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4366. doi:10.1158/1538-7445.AM2013-4366