Targeting tachykinin receptors in neuroblastoma.

// Anton G. Henssen 1, * , Andrea Odersky 2, * , Annabell Szymansky 3 , Marleen Seiler 4 , Kristina Althoff 2 , Anneleen Beckers 5 , Frank Speleman 5 , Simon Schafers 2 , Katleen De Preter 5 , Kathy Astrahanseff 3 , Joachim Struck 4 , Alexander Schramm 2 , Angelika Eggert 3, 6 , Andreas Bergmann 4 , Johannes H. Schulte 3, 6 1 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, USA 2 Department of Pediatric Oncology and Hematology, University Children’s Hospital Essen, Germany 3 Department of Pediatric Oncology/Hematology, Charite- Universitatsmedizin Berlin, Germany 4 Sphingotec GmbH, Hennigsdorf, Germany 5 Center of Medical Genetics Ghent (CMGG), Ghent University Hospital, Belgium 6 German Consortium for Translational Cancer Research (DKTK), Partner Site Charite Berlin, Berlin, Germany * These authors contributed equally to this work Correspondence to: Anton G. Henssen, email: henssena@mskcc.org Keywords: fosaprepitant, aprepitant, neuroblastoma, NK1R, targeted therapy Received: June 29, 2016      Accepted: November 12, 2016      Published: November 18, 2016 ABSTRACT Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1 , and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma.