Targeting tyrosine receptor kinase B in gliomas

Kv, Pinheiro; Alves, Camila Pereira; Buendia, Marienela; Ms, Gil; Thomaz, Amanda Cristina Godot; Schwartsmann, Gilberto; Farias, Caroline Brunetto de; Roesler, Rafaël; Rl, Bowman; Wang, Q; Carro, A; Rg, Verhaak; Squatrito, Massimo

doi:10.1093/neuonc/now199

“…To increase our understanding of the functional role of TrkB in MB, here we evaluated cellular changes possibly associated with the antitumoral effects of TrkB inhibition in vitro and in vivo . ANA-12 has been successfully used to target TrkB in preclinical studies of other types of tumors, including lung cancer, Ewing sarcoma, glioblastoma, oral squamous carcinoma, and leukemia (Polakowski et al, 2014; Sinkevicius et al, 2014; Heinen et al, 2016; Pinheiro et al, 2017; Moriwaki et al, 2018). The present study is the first to evaluate the antitumoral effects of ANA-12 in a pediatric cancer animal model.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

Thomaz

¹

,

Pinheiro

²

,

Souza

³

et al. 2019

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Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker β-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.

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“…TrkA and TrkB can be activated in GBM cells, and combined inhibition of Trk and c-Met reduces the resistance against CDK4/6 inhibition in experimental GBM [64]. Selective TrkB inhibition effectively and dose-dependently impairs the viability of human GBM cells in vitro [65]. A systematic screening of a library of human tyrosine kinases for their oncogenic potential in glioma and found compelling evidence indicating that TrkB plays a role in tumor formation [66].…”

Section: Neurotrophin Signaling In Cancermentioning

confidence: 99%

Neurotrophin Signaling in Medulloblastoma

Thomaz

¹

,

Jaeger

²

,

Brunetto

³

et al. 2020

Cancers

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Neurotrophins are a family of secreted proteins that act by binding to tropomyosin receptor kinase (Trk) or p75NTR receptors to regulate nervous system development and plasticity. Increasing evidence indicates that neurotrophins and their receptors in cancer cells play a role in tumor growth and resistance to treatment. In this review, we summarize evidence indicating that neurotrophin signaling influences medulloblastoma (MB), the most common type of malignant brain cancer afflicting children. We discuss the potential of neurotrophin receptors as new therapeutic targets for the treatment of MB. Overall, activation of TrkA and TrkC types of receptors seem to promote cell death, whereas TrkB might stimulate MB growth, and TrkB inhibition displays antitumor effects. Importantly, we show analyses of the gene expression profile of neurotrophins and their receptors in MB primary tumors, which indicate, among other findings, that higher levels of NTRK1 or NTRK2 are associated with reduced overall survival (OS) of patients with SHH MB tumors.

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“…We also observed an 1.8-fold change increase in TUBB3 mRNA levels in UW228 cells (Figure 6E), however, there were no differences in the protein content of TUBB3 (Figure 6F, 6G). These findings (Polakowski et al, 2014;Sinkevicius et al, 2014;Heinen et al, 2016;Pinheiro et al, 2017;Moriwaki et al, 2018). The present study is the first to evaluate the antitumoral effects of ANA-12 in a pediatric cancer animal model.…”

Section: Differentiation and Pluripotency Markersmentioning

confidence: 87%

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

Thomaz

¹

,

Pinheiro

²

,

Souza

³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker β-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.

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Targeting tyrosine receptor kinase B in gliomas

Cited by 17 publications

References 10 publications

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

Neurotrophin Signaling in Medulloblastoma

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

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