Targeting tachykinin receptors in neuroblastoma.

Anton G Henssen,Anneleen Beckers,Frank Speleman,Marleen Seiler,Andreas Bergmann,Alexander Schramm,Simon Schäfers,Annabell Szymansky,Katleen De Preter,Andrea Odersky,Angelika Eggert,Kathy Astrahanseff,Johannes H Schulte,Joachim Struck,Kristina Althoff

doi:10.18632/oncotarget.13440

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.

Highlights

Neuroblastoma is the most common extracranial solid tumor in children
TACR1 protein was expressed in all human neuroblastoma cell lines assessed, expression levels varied between cell lines, with SY5Y expressing only low levels and IMR5 strongly expressing TACR1 (Figure 1A, 1B and 1E)
Based on the observed TACR1 expression and previous reports of TACR1 mitogenic properties in other tumor entities we hypothesized that TACR1 activity might exhibit mitogenic functions in a subset of neuroblastoma cells through activation of SRC and other downstream targets and that pharmaceutically inhibiting TACR1 could be a therapeutic option in these cells

Summary

Introduction

Neuroblastoma is the most common extracranial solid tumor in children. Polychemotherapy is a wellestablished part of first-line therapy for patients with metastatic neuroblastomas [1]. Additional therapeutic strategies that lower toxicity and/or improve efficacy of current treatment, such as novel drug combination regimens are desperately needed to improve survival and long-term quality of life during long-term survival in high-risk neuroblastoma patients. Fosaprepitant (Ivemend), is a water-soluble phosphoryl prodrug of aprepitant, which is intravenously administered [5]. These drugs are used in clinical practice as antiemetics for neuroblastoma patients receiving emetogenic chemotherapy agents including platinum-based chemotherapeutics [3], and no considerable side effects have been observed. Pharmacokinetic analysis showed that intravenous administration of 115 mg fosaprepitant in patients results in peak concentrations of ~3000 ng/ml blood, equivalent to approximately a 5 μM concentration in circulating blood leading to over 90% TACR1 receptor occupancy by aprepitant. High aprepitant concentrations are tolerated without causing considerable side effects [5]

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