BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment.

Tropomyosin-Related Kinase Receptor and Neurotrophin Expression in Cutaneous Melanoma Is Associated with a Poor Prognosis and Decreased Survival

“…The involvement of NTs and TRKs in oncogenesis has been investigated in several types of tumors [32-40], and NT activation of TRK receptors has been shown to be involved in early-stage malignancy development, metastasis, and resistance to treatment [41-44]. In an IHC study of 15 cutaneous melanomas, 12 melanoma metastases, and 16 benign pigment cell lesion samples, Innominato et al [22] found that the expression of NGF, BDNF, NT-3, and their receptors (p75, TrkB, and TrkC) was more frequent in cutaneous melanoma and metastasis samples than in benign lesions or normal skin [22].…”

Neuronal Activity in Ontogeny and Oncology

“…Recent studies showed that p75NTR is expressed predominantly in the SHH subgroup [107], but the functional consequence of this remains to be determined. BDNF and TrkB signaling effects in medulloblastoma are even less clear, with one study reporting exposure to BDNF and reduced viability in human medulloblastoma cell lines [108]; but another study reporting a similar effect with TrkB inhibition [109]. The function of neurotrophin signaling in ependymomas is also an area that requires investigation.…”

Targeting tyrosine receptor kinase B in gliomas

“…7 Another recent study has suggested that glioma growth may be regulated by TrkB expressed in exosomes. 8 We have recently provided evidence for a potential role of TrkB inhibition as a strategy to reduce cell proliferation and potentiate the effects of chemotherapy in medulloblastoma 9 and Ewing sarcoma. 10 In order to investigate the antitumor effects of pharmacological inhibition of TrkB-associated signaling, Ni et al used the compounds AZD1480, a janus kinase (JAK) inhibitor, and RXDX-101, which nonselectively inhibit different members of the Trk receptor family (TrkA, TrkB, and TrkC), C-ros oncogene 1 (ROS1), and the anaplastic lymphoma kinase (ALK).…”