INTRODUCTION
Children with relapsed/refractory primary central nervous system (CNS)
tumors have a dismal prognosis, and there is a critical need for novel
therapeutics. Cyclin-dependent kinases (CDKs) represent an appealing
target. CDKs coordinate the transition between different stages of the
cell cycle, and they are regulated by cyclins. Recent studies have shown
that a significant subset of pediatric CNS tumors harbor mutations in
the CDK4/6 signaling axis.1-3 CDK4 and CDK6 drive the
transition from the G1 growth phase to chromosomal replication in the S
phase, and they are regulated by cyclins D1, D2, D3, and
E.4 A central node in the G1 to S transition is the
retinoblastoma (Rb) protein. In an unphosphorylated state, Rb sequesters
E2F transcription factors that drive cells through the S phase.
Phosphorylation of Rb by CDK4/6 releases the E2F transcription factors,
which results in progression of the cell cycle through S
phase.4 This transition is very carefully regulated to
prevent mutated cells from progressing through mitosis in normal cells.
However, this process is corrupted in pediatric CNS tumors by a variety
of mechanisms including genetic loss of RB1 , amplification ofCCND1 , and deletion of genes encoding CDK inhibitors such asCDKN2a .5
Palbociclib (IBRANCE®, Pfizer Inc, Kenilworth, NJ) is
an orally bioavailable, highly specific inhibitor of CDK4/6. Palbociclib
exhibits pH-dependent solubility and high permeability. Palbociclib is
FDA-approved for the treatment of advanced or metastatic breast cancer
in combination with either fulvestrant or
letrozole.6,7 Preclinical studies of palbociclib in a
variety of CNS tumor cell lines and patient-derived xenograft mouse
models demonstrated efficacy.8-11 Additionally,
preclinical studies confirmed that palbociclib could penetrate the
blood-tumor barrier and that intact Rb is required for its therapeutic
effect.8 Here we report the results of a phase I trial
assessing safety and efficacy of palbociclib in children with brain
tumors (PBTC-042).