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

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.

JAK/STAT signaling in hepatocellular carcinoma

“…Thus, these findings indicate a strong correlation between WP1066 and programmed cell death. Currently, WP1066 is being investigated for brain metastasis in clinical trials (NCT01904123) [83,86]. Similarly, another study by Tsujita et al showed that WP1066 demonstrated efficacy by promoting apoptosis of bladder cancer cells [84].…”

“…Pacritinib was also well tolerated and adverse events were uncommon, with patients generally presenting mild gastrointestinal toxic effects. In another study, Jensen and colleagues used patient-derived brain tumor-initiating cells and demonstrated that pacritinib was able to reduce cell viability in these cells with satisfactory results [86]. Moreover, the team determined the compatibility of pacritinib in combination with temozolomide, the current standard of care chemotherapy for glioblastoma multiforme.…”

Role of Macrophages in Brain Tumor Growth and Progression

“…The expression of STAT-3 (Signal Transducer and Activator of Transcription 3) could be considered a marker for M2 polarized GAMs and it is activated in GBMs cells as well. The JAK2/STAT-3 pathway regulates many cellular processes in GBM, including cell survival, proliferation, invasion, anti-apoptosis, and immune evasion making STAT-3 a possible target of therapy [ 92 , 93 ].…”

A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier

“…The activation of STAT3 is associated with a worse prognosis and more aggressive disease than those with lower levels of activated STAT3 [ 7 , 8 , 9 ]. Inhibition of STAT3 has been reported to inhibit proliferation of GBM cells and attenuate resistance to temozolomide, which has translated into survival benefits based on in vivo models [ 10 , 11 , 12 , 13 , 14 , 15 ].…”