ET-35 * PACRITINIB: A NOVEL JAK/STAT INHIBITOR WITH TRANSLATIONAL RELEVANCE FOR GBM

Abstract

Glioblastoma multiforme (GBM) is characterized by an aggressive clinical course, therapeutic resistance, and striking molecular heterogeneity. GBM-derived brain tumor initiating cells (BTICs) closely model this molecular heterogeneity and may have a key role in tumor recurrence and therapeutic resistance. Recent evidence, from our lab and others, indicates that the Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway is an important mediator of tumor cell survival, growth, and invasion in a large group of GBMs. Thus, inhibition of the JAK/STAT3 pathway may hold great promise as a therapeutic strategy for GBM. However, to date, drugs targeting activated STAT3 in clinically relevant models have not been successfully transitioned into clinical studies. Here we investigated the efficacy of a novel JAK/STAT inhibitor, Pacritinib, in BTIC lines cultured from GBM patients. Pacritinib is currently in a multicenter, randomized, Phase 3 trial comparing its efficacy and safety with that of best available therapy in patients with primary myelofibrosis. In GBM BTICs, Pacritinib administration resulted in on-target JAK2/STAT3 inhibition at 1-2 muM that dramatically reduced cell survival in a large number of lines, regardless of endogenous MGMT promoter methylation or EGFR, PTEN, and TP53 mutational status. Pacritinib was also found to cross the blood-brain barrier in NOD-SCID mice, by liquid chromatography-mass spectrophometry, with no toxicity observed on repeated administration of up to 200mg/kg per day by oral gavage. Previous studies on different JAK/STAT3 inhibitors, by others and us, demonstrated toxicity at doses required to shut-off STAT3 signaling and achieve tumour cell death in vivo. We are currently investigating the actions of Pacritinib in orthotopic BTIC xenograft animal survival studies. Given its previously established human safety profile and demonstrated activity in the clinically relevant BTIC model, Pacritinib may hold considerable promise for clinical translation in GBM.