Abstract
Embryonal tumor with multilayered rosettes (ETMR) is a rare and very aggressive brain tumor occurring in children less than 4 years of age. The survival is poor, with the best reported 1 year EFS and OS of 36% and 45%, respectively. EMTR demonstrates amplification of the miRNA cluster C19MC (95%) and high expression of LIN28A/LIN28B proteins. Since the LIN28 pathway is targeted and suppressed by DFMO (diflouromethylornithine), patients with ETMR were treated with DFMO and evaluated for safety and response. METHODS: One patient received DFMO through an EIND, followed by 7 additional patients enrolled on the Beat Childhood Cancer Consortium Expanded Access protocol for LIN28 driven tumors (NCT03581240). Patients received DFMO alone or in combination with another agent and/or radiation. Patients were seen monthly for safety and evaluated by MRI every 2–3 months. DNA exome and RNA sequencing was performed in 7 patients. Two patient cell lines and xenograft models were established. RESULTS: Three of 8 patients were treated at the completion of upfront intensive multimodal therapy and all remain in remission between 0.5–1.25 yrs to date. The remaining 5 patients enrolled following disease progression or relapse. Of these, one patient completed 2 years of DFMO and remains in remission 2 years off therapy, 3 remain on DFMO and with NED/SD between 0.25–1.1 years, and one patient experienced PD at 3 months. DFMO was well tolerated either alone or when combined with radiation, vorinostat, everolimus, etoposide or temozolomide. No SAEs related to DFMO have been reported. Adverse events included anemia, diarrhea, and reversible hearing loss. RNA sequencing showed activation of ODC/MYC/LIN28 pathway. CONCLUSION: Treatment with DFMO in children with ETMR was well tolerated and appears to confer clinical benefit with prolonged survival. Based on these results, a prospective clinical trial is ongoing through the Beat Childhood Cancer consortium.