Presentation Title

Inhibition of RET via BLU-667 in an in vitro Model of Neuroblastoma

Faculty Mentor

Peter Zage

Start Date

23-11-2019 10:00 AM

End Date

23-11-2019 10:45 AM

Location

61

Session

poster 3

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

Neuroblastoma is the most common extracranial solid tumor of childhood. Despite aggressive treatment, outcomes in patients with high-risk disease remains poor and new therapeutics are needed to address their needs. Rearranged during Transfection (RET) is a tyrosine kinase that is a known oncogenic driver of multiple human tumors. RET is expressed on neural crest derived cells, including neuroblastoma cells, and has been shown to play a role in neuroblastoma proliferation and survival as well. Recent studies have shown RET inhibition to be a promising new therapeutic target in neuroblastoma. BLU-667 is a selective RET inhibitor with a higher potency and specificity for RET than the current inhibitors that have been previously tested. We hypothesize that this increased potency and specificity will result in greater efficacy against neuroblastoma in preclinical models with fewer off target effects. Thus, to investigate this we evaluated BLU-667 at different concentrations against a panel of established human neuroblastoma cell lines to assess its effects on neuroblastoma cell proliferation, differentiation, and viability. We found that inhibition of RET resulted in a significant decrease in cell proliferation and viability in vitro. Further, given the increased specificity of BLU-667 to RET, we hope to use western blot protein analysis to establish the specific downstream pathways through which RET inhibition leads to decreased neuroblastoma cell survival, potentially revealing further therapeutic targets.

This research was supported by NCI of NIH: U54CA132384 & U54CA132379. The content is the responsibility of the authors and does not represent the official views of the National Institutes of Health.

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Nov 23rd, 10:00 AM Nov 23rd, 10:45 AM

Inhibition of RET via BLU-667 in an in vitro Model of Neuroblastoma

61

Neuroblastoma is the most common extracranial solid tumor of childhood. Despite aggressive treatment, outcomes in patients with high-risk disease remains poor and new therapeutics are needed to address their needs. Rearranged during Transfection (RET) is a tyrosine kinase that is a known oncogenic driver of multiple human tumors. RET is expressed on neural crest derived cells, including neuroblastoma cells, and has been shown to play a role in neuroblastoma proliferation and survival as well. Recent studies have shown RET inhibition to be a promising new therapeutic target in neuroblastoma. BLU-667 is a selective RET inhibitor with a higher potency and specificity for RET than the current inhibitors that have been previously tested. We hypothesize that this increased potency and specificity will result in greater efficacy against neuroblastoma in preclinical models with fewer off target effects. Thus, to investigate this we evaluated BLU-667 at different concentrations against a panel of established human neuroblastoma cell lines to assess its effects on neuroblastoma cell proliferation, differentiation, and viability. We found that inhibition of RET resulted in a significant decrease in cell proliferation and viability in vitro. Further, given the increased specificity of BLU-667 to RET, we hope to use western blot protein analysis to establish the specific downstream pathways through which RET inhibition leads to decreased neuroblastoma cell survival, potentially revealing further therapeutic targets.

This research was supported by NCI of NIH: U54CA132384 & U54CA132379. The content is the responsibility of the authors and does not represent the official views of the National Institutes of Health.