Trk-Targeted Therapy of Human Neuroblastomas
Background
Neuroblastoma (NB) is the most common solid tumor of childhood, accounting for 8-10% of childhood cancers, and 15% of deaths from childhood cancer. Most patients have high-risk disease and a poor prognosis, despite aggressive, multimodality therapy. Therefore, more effective, less toxic therapy is needed, and targeted agents hold great promise in terms of achieving this goal. We have shown that the Trk family of neurotrophin receptors plays important roles in the behavior of NBs. We have shown in a phase 1 clinical trial that inhibiting TrkB in NB patients with recurrent/refractory disease can produce durable responses lasting 1-2 years, with no clinical toxicity. However, the agent used is no longer available, so new and more specific Trk inhibitors are needed.
Project Goals
We are testing two novel, highly potent and selective Trk inhibitors in our laboratory, and we propose to investigate one or both of these agents in preclinical and in clinical trials. First, we will test the Trk inhibitor in culture and in an animal model of NB alone and in combination with other agents. Second, we will generate resistant clones and determine how they became resistant. Third, we will conduct a phase 1 clinical trial with the Trk inhibitor, and correlate the response to whether or not the tumor expresses Trk the. These studies will inform future phase 1 studies for all Trk-positive tumors in pediatrics, as well as combination studies of a Trk inhibitor with other agents, as tested in our preclinical model.
