Bromodomain and Extra-Terminal Protein Inhibitors: Biologic Insights and Therapeutic Potential in Pediatric Brain Tumors.

Pediatric brain tumors have surpassed leukemia as the leading cause of cancer-related death in children. Several landmark studies from the last two decades have shown that many pediatric brain tumors are driven by epigenetic dysregulation within specific developmental contexts. One of the major determinants of epigenetic control is the histone code, which is orchestrated by a number of enzymes categorized as writers, erasers, and readers. Bromodomain and extra-terminal (BET) proteins are reader proteins that bind to acetylated lysines in histone tails and play a crucial role in regulating gene transcription. BET inhibitors have shown efficacy in a wide range of cancers, and a number have progressed to clinical phase testing. Here, we review the evidence for BET inhibitors in pediatric brain tumor experimental models, as well as their translational potential.

A modified IRS-III chemotherapy regimen leads to prolonged survival in children with embryonal tumor with multilayer rosettes.

BACKGROUND: Embryonal tumor with multilayer rosettes (ETMR) is a rare CNS malignancy affecting young children that carries a very poor prognosis. Treatment with intensive surgical resection, radiotherapy, and high-dose chemotherapy is insufficient treatment in the vast majority of cases. Effective, biologically based therapies for this tumor are therefore desperately needed. The Dana-Farber Cancer Institute-modified IRS-III protocol incorporates preclinically active agents, such as doxorubicin and actinomycin D, into the treatment regimen for ETMR and may improve patient outcomes. METHODS: The authors present a case series of 5 children with ETMR treated with an IRS-III-based chemotherapy backbone. RESULTS: All 5 patients received a gross-total tumor resection. Patients received between 12 and 51 weeks of IRS-III therapy at the discretion of their treating physician. Four patients received focal radiation therapy, with the fifth patient instead receiving a cycle of high-dose chemotherapy with autologous stem cell rescue. Four patients have progression-free survival of more than 18 months. Chemotherapy treatment was reasonably tolerated by all 5 patients with one case of mild sinusoidal obstructive syndrome and one case of Grade 3 peripheral neuropathy. CONCLUSIONS: The patient outcomes in this small cohort are far better than would be expected based on the historical survival for this tumor. Given the tremendous need for effective therapy for ETMR, further investigation of this approach is warranted. An international consensus protocol based on the IRS-III regimen has been developed and will be available through a multicenter clinical trial and a global treatment registry.