title: Targeting tachykinin receptors in neuroblastoma.
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.
authors.affiliation: Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Anton G
authors.initials: AG
authors.lastname: Henssen
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Odersky
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité- Universitätsmedizin Berlin, Germany.
authors.forename: Annabell
authors.initials: A
authors.lastname: Szymansky
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany.
authors.forename: Marleen
authors.initials: M
authors.lastname: Seiler
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Althoff
authors.affiliation: Center of Medical Genetics Ghent (CMGG), Ghent University Hospital, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Beckers
authors.affiliation: Center of Medical Genetics Ghent (CMGG), Ghent University Hospital, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schäfers
authors.affiliation: Center of Medical Genetics Ghent (CMGG), Ghent University Hospital, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité- Universitätsmedizin Berlin, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Astrahanseff
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Struck
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité- Universitätsmedizin Berlin, Germany.|German Consortium for Translational Cancer Research (DKTK), Partner Site Charite Berlin, Berlin, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.affiliation: Sphingotec GmbH, Hennigsdorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergmann
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité- Universitätsmedizin Berlin, Germany.|German Consortium for Translational Cancer Research (DKTK), Partner Site Charite Berlin, Berlin, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077608:Aprepitant; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D050703:E2F2 Transcription Factor / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D009025:Morpholines / Q000627:therapeutic use*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs; D018040:Receptors, Neurokinin-1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077608:Aprepitant; C579707:fosaprepitant
keywords: NK1R; aprepitant; fosaprepitant; neuroblastoma; targeted therapy