CNSC-35. EVALUATING THE THERAPEUTIC POTENTIAL OF NOVEL NTRK AGONISTS AND ANTAGONISTS IN HIGH-RISK NEUROBLASTOMA

Abstract

Abstract Neuroblastoma is the most common extra-cranial tumor diagnosed in children within the first two years of their lives. Although low-risk and intermediate -risk neuroblastoma patients have a survival rate of 90-95%, high-risk neuroblastoma patients have a survival rate of approximately 50%. To improve the survival rate in high-risk patients, our group focuses on tropomyosin receptor kinases (TRKs), which are family of tyrosine kinases that have been heavily implicated in crucial developmental processes, such as differentiation, that are typically hijacked in cancer. Using de novo agonists specifically designed against three different neurotrophin receptors (TrkA, TrkB, TrkC), our group is investigating the fundamental biological role of TRK receptors in mediating tumorigenesis in neuroblastoma. Preliminary results show that our TrkA agonist not only increase both ERK and AKT activity but also causes a significant decrease in TrkA expression in several neuroblastoma cell lines which we hypothesize is due to constitutive activation of TrkA, leading to its internalization and degradation. Phenotypically, we observe that neuroblastoma cell line SK-N-SY5Y, which is typically used in differentiation studies, lose their neuroblast-like phenotype when treated with TrkA agonist, and begin to exhibit neurite outgrowth which may be indicative of differentiation-associated pathways being activated due to TrkA activation. Using a combination of de novo protein design, immunoblotting, RNA-sequencing, and in vivo studies to characterize the effect(s) TRK agonists have on neuroblastoma, we hope to assess whether targeting and modifying the activity of TrkA, and other Trk receptors such as TrkB and TrkC, holds new therapeutic promise for patients with high-risk neuroblastoma.