Trk-Targeted Therapy of Human Neuroblastomas
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.
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.
2015 Project Update:
The majority of high-risk neuroblastoma (NB) patients still do not survive, despite maximally intensive, multimodality therapy. Therefore, more effective, less toxic therapy is needed. One approach has been to develop agents that target a specific gene, protein or pathway that is critical to tumor cell survival or behavior. We have identified a family of three proteins called TRKs (pronounced “tracks”) that play an important role in the behavior of neuroblastomas, as well as other cancer types in children and adults. We had previously tested an inhibitor of TRKs that proved effective in treating recurrent/refractory neuroblastomas in a phase 1 clinical trial, but support for this agent was discontinued due to corporate takeover. We have tested a number of other TRK inhibitors since then, and we identified RXDX101 (Entrectinib), provided by Ignyta, Inc. as a potent, TRK-elective multikinase inhibitor. We have an agreement to perform a limited institution phase 1 clinical trial, collaborating with the three other institutions that have Center of Excellence Grants from ALSF (Boston, Baylor, UCSF). This clinical trial is planned to begin in the fall of 2015, barring unforeseen administrative hurdles. In order to support this trial, we need to develop tests to identify neuroblastomas and other pediatric solid tumors in which TRK genes are activated by mutations, translocations, or overexpression (making too much of the protein). We also need to determine the mechanisms by which tumor cells become resistant to Entrectinib, so we can prevent or overcome this. Finally, we need to identify combinations of Entrectinib with other conventional or biological agents that are more effective than either alone. Together, this information will allow us to interpret the responses (or lack thereof) to this Entrectinib, prevent or overcome resistance to this agent, and plan for future clinical trials that combine Entrectinib with other agents.