The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model

PLoS One. 2017 Dec 18;12(12):e0189670. doi: 10.1371/journal.pone.0189670. eCollection 2017.

Abstract

Purpose: The 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 design: The 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.

Results: In 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.

Conclusion: This 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.

MeSH terms

  • Animals
  • Apoptosis
  • Blood-Brain Barrier / drug effects
  • Brain Neoplasms / drug therapy*
  • Bridged-Ring Compounds / therapeutic use*
  • Cell Proliferation
  • Cell Survival
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Disease Progression
  • Female
  • Glioblastoma / drug therapy*
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, SCID
  • Microsomes, Liver / drug effects
  • Permeability
  • Pyrimidines / therapeutic use*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Temozolomide
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • Bridged-Ring Compounds
  • Pyrimidines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Dacarbazine
  • JAK2 protein, human
  • Janus Kinase 2
  • Temozolomide

Grants and funding

This work was supported by Terry Fox Research Institute to HAL and SW, http://www.tfri.ca/; Stem Cell Network of Canada to HAL and SW, http://stemcellnetwork.ca/; Cell Therapeutics Inc Biopharma to HAL and SW, http://www.ctibiopharma.com/; Canadian Institutes of Health Research (Scholarship to KVJ), http://www.cihr-irsc.gc.ca/e/193.html; Alberta Cancer Foundation (Scholarship to KVJ), http://albertacancer.ca/. Please note that we do not have grant numbers in Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.