Abstract
PurposeThe prognosis for patients diagnosed with glioblastoma multiforme (GBM) remains dismal, with current treatment prolonging survival only modestly. As such, there remains a strong need for novel therapeutic strategies. The janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 pathway regulates many cellular processes in GBM, including survival, proliferation, invasion, anti-apoptosis, and immune evasion. Here, we evaluated the preclinical efficacy of pacritinib, a novel compound targeting JAK2, using a collection of diverse patient-derived brain tumor initiating cells (BTICs).Experimental designThe effects of pacritinib on BTIC viability and sphere forming capacity were evaluated in vitro using the alamarBlue and neurosphere assays, respectively. On-target inhibition of JAK2/STAT3 signaling was investigated using western blotting. The efficacy of pacritinib was tested in vivo in pharmacokinetic analyses, liver microsome analyses, and Kaplan-Meier survival studies.ResultsIn vitro, pacritinib decreased BTIC viability and sphere forming potential at low micromolar doses and demonstrated on-target inhibition of STAT3 signaling. Additionally, pacritinib was found to improve the response to temozolomide (TMZ) in TMZ-resistant BTICs. In vivo, systemic treatment with pacritinib demonstrated blood-brain barrier penetration and led to improved overall median survival in combination with TMZ, in mice orthotopically xenografted with an aggressive recurrent GBM BTIC culture.ConclusionThis preclinical study demonstrates the efficacy of pacritinib and supports the feasibility of testing pacritinib for the treatment of GBM, in combination with the standard of care TMZ.
Highlights
Glioblastoma multiforme (GBM), a World Health Organization (WHO) grade IV astrocytoma, is the most common and lethal central nervous system tumor [1,2]
Systemic treatment with pacritinib demonstrated blood-brain barrier penetration and led to improved overall median survival in combination with TMZ, in mice orthotopically xenografted with an aggressive recurrent GBM brain tumor initiating cells (BTICs) culture
Targeting JAK2/signal transducer and activator of transcription 3 (STAT3) signaling with pacritinib in GBM BTICs
Summary
Glioblastoma multiforme (GBM), a World Health Organization (WHO) grade IV astrocytoma, is the most common and lethal central nervous system tumor [1,2]. It is a rare disease, with 2–4 new GBM diagnoses per 100,000 in North America every year. Disease recurrence has been postulated to be due to the presence of brain tumor initiating cells (BTICs). BTICs have the cancer stem cell properties of long-term self-renewal, multi-lineage differentiation, and the capability to readily initiate tumors in mice that are similar to the human GBMs from which they were derived [5,6]. In order to prevent post-treatment recurrence, targeting BTICs is likely a crucial therapeutic strategy to make this devastating disease more manageable
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