Trk Expression and Inhibition in Neuroblastoma

Background:

Neuroblastoma (NB) is the most common and deadly solid tumor in children. Clinical heterogeneity, from spontaneous regression to relentless progression, is a characteristic feature of this pediatric cancer. Our laboratory and others provided evidence suggesting that the NTRK family of neurotrophin receptors plays critical roles in NB pathogenesis and clinical behavior. NTRK1 (TrkA) is expressed in favorable neuroblastomas and likely contributes to the spontaneous regression or differentiation seen in these tumors. Conversely, coexpression of NTRK2 (TrkB) and its ligand, brain-derived neurotrophic factor (BDNF) in unfavorable NBs creates an autocrine survival pathway that leads to aggressive behavior, including invasion, metastasis, angiogenesis and drug resistance. The laboratory of Garrett M. Brodeur hypothesizes that targeting the TrkB/BDNF pathway with TRK inhibitors (TRKIs) will effectively kill TrkB-expressing NB cells, as well as render them more susceptible to killing by conventional chemotherapy. These studies will lead to more effective and less toxic approach to treating high-risk NBs.

Project Goal:

I will learn sterile cell culture techniques and propagate Trk-null NB cells, as well as clones expressing either TrkA or TrkB. I will demonstrate ligand-activated phosphorylation of these receptors, as well as the phosphorylation of nodal downstream signaling pathways (PI3K/AKT, MEK/ERK). I will assess the differential effects of TrkA or TrkB activation on cell survival, proliferation, morphology and differentiation. Finally, I will demonstrate the consequences of inhibiting these pathways with Trk-selective inhibitors, which are being developed as biologically targeted therapy for NBs in clinical trials.