Tyrosine Kinase Inhibitors for the Treatment of Neuroblastoma
Garrett Brodeur, MD, has shown that the TRK neurotrophin receptors play critical roles in the behavior of neuroblastomas. TrkA is expressed at high levels in more favorable neuroblastomas, especially in infants, and the TrkA/NGF signaling pathway may be responsible for the spontaneous regression seen in some of these patients. Conversely, TrkB is expressed at high levels in more aggressive neuroblastomas, especially those with MYCN amplification. These cells also express the TrkB ligand, brain-derived neurotrophic factor (BDNF), and this autocrine pathway leads to invasion, angiogenesis, metastasis, and drug resistance. Thus, the TrkB/BDNF autocrine pathway is an oncogenic driver of high-risk neuroblastomas, and should be an excellent therapeutic target for inhibition.
Dr. Brodeur and researchers at the Center for Childhood Cancer Research (CCCR) have conducted preclinical studies on compounds that inhibit the TRK receptors. The completed preclinical work on a pan-TRK inhibitor, called Lestaurtinib, led to a clinical trial of this agent. The results were very promising, with about half the patients experiencing a durable response lasting more than 10 months, and with virtually no symptoms. However, the company that provided Lestaurtinib was purchased by another company and development of the drug was discontinued.
Dr. Brodeur and colleagues have investigated a number of other possible pan-TRK inhibitors, but two have emerged as superior in their preclinical studies (Entrectinib, from Ignyta, Inc.; and LOXO-101, from LOXO Oncology). Entrectinib inhibits all TRK receptors (TrkA, TrkB and TrkC), but it also is a potent inhibitor of ALK and ROS1, two other receptor tyrosine kinases related to the TRK family, whereas LOXO-101 mainly inhibits the TRK receptors. Because ALK can also be activated in neuroblastomas, Entrectinib has been chosen to move into a Phase 1 clinical trial, which just started in early 2016.
The CCCR and The Children’s Hospital of Philadelphia are conducting this trial, in collaboration with with three other cancer centers that are part of an Alex’s Lemonade Stand Foundation (ALSF) Centers of Excellence grant program. They are conducting this pediatric trial in patients with recurrent/refractory solid tumors, and assessing the safety and toxicity of Entrectinib. The trials are recruiting patients with any solid tumor — not just neuroblastoma — because TRK is expressed on many other types of solid tumor cells, including sarcomas and brain tumors. We anxiously await the results of this trial.