ATPS-52A PRE-CLINICAL COMBINATORIAL STRATEGY TO TARGET THE JAK/STAT AND EGFR PATHWAYS IN GBM

Glioblastoma multiforme (GBM), characterized by an aggressive clinical course, therapeutic resistance and striking molecular heterogeneity, remains incurable. A large number GBMs have EGFR alterations and, despite poor clinical translation to date, EGFR inhibition remains of therapeutic relevance. Recent evidence, from our group and others, indicates that JAK2/STAT3 pathway is an important mediator of tumor cell survival, growth, and invasion in GBM. Interestingly, EGFR inhibition leads to activation of survival-signalling pathways such as STAT3, diminishing effectiveness of EGFR inhibition. We investigated the efficacy of a novel JAK2 inhibitor, pacritinib, in brain tumour initiating cell (BTIC) lines to evaluate potential use in the treatment of GBM patients. In a Phase III study of patients with myelofibrosis, pacritinib demonstrated manageable toxicity and clinically and statistically improved patient spleen volume and patient reported outcomes. Pacritinib results in on-target JAK2/STAT3 inhibition at 1-2 µM and dramatically reduces BTIC proliferation, regardless of endogenous MGMT promoter methylation or EGFR, PTEN, and TP53 mutational status. Pacritinib in combination with temozolomide prolongs survival, over either drug alone, in orthopically xenografted NOD-SCID. We are testing the hypothesis that concurrent inhibition of JAK/STAT and EGFR signalling may be an effective, clinically relevant therapeutic, strategy for GBM. We examined the in vitro actions of pacritinib on BTICs, in combination with three clinically approved EGFR inhibitors, erlotinib, afatinib and lapatinib and are investigating other clinically relevant EGFR inhibitors for GBM. Combinatorial treatment with pacritinib and EGFR inhibitors shows striking responses, with lowered IC50s and BTIC viability. The combinatorial actions of EGFR and STAT3 inhibition were particularly effective in BTIC lines with EGFR activating vIII and missense point mutations. On target activity was demonstrated with reduced phospho-EGFR, phospho-STAT3 and effectors of both pathways. Current studies are aimed at investigating the combined actions of Pacritinib and EGFR inhibitors, over single agents, in orthotopic xenograft animal survival.

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