The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

Abstract

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.

Targeting the JAK-STAT pathway in lymphoma: a focus on pacritinib

“…In fact, preclinical studies suggest that JAK inhibitors synergize with bcl-2 inhibitors both in MPNs and lymphoma in in vitro and in vivo models [93,94]. Synergism with MEK and histone deacetylase (HDAC) inhibitors has been also reported in in vitro HL models and MPNs, respectively [73,95,96]. On the other hand, the GI toxicity observed [79,80] Phase II (MPNs) -JAK2, JAK1, JAK3 JNK, CDK2 Thrombocytopenia, transaminasemia, hyperlipase/amylasemia, neuropathy LY2784544 [81] Phase I/II (MPNs) -Selective JAK2V617F Nausea, diarrhea, anemia, increased creatinine XL019 [82] Stopped (MPNs) -JAK2, JAK1, JAK3 Peripheral neuropathy BMS911543 [84] Phase I/II (MPNs) -JAK2 NA NS-018 [83] Phase I/II ( …”

JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease

“…Furthermore, studies with JAK2 V617F -mutant cells showed that pan-deacetylase inhibition enhanced suppression of JAK/STAT signaling by a JAK2 inhibitor, and the combination exerted synergistic apoptosis induction (16). Finally, in JAK2-or FLT3-mutant acute myelogenous leukemia (AML) xenograft models, the HDAC inhibitor pracinostat displayed synergistic tumor growth inhibition in combination with the dual JAK2/FLT3 inhibitor pacritinib (31).…”

Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance

“…Pracinostat as single agent reduced the plasma MCP-1 level by 40% while 10% reduction was seen upon pacritinib treatment. The combined treatment reduced the defined cytokine plasma level by 69% or 53 pg/ml (Novotny-Diermayr et al 2012).…”

“…Many HDACi Okabe et al (2013) including pracinostat have shown encouraging result in AML and myelodysplastic syndrome but the desired efficacy is not achieved with these inhibitors as single agents (monotherapy) (Prebet & Vey 2011). Pracinostat has shown marvellous anticancer effect in AML models in combination therapy with pacritinib (JAK2/FLT3 kinase inhibitor) (Novotny-Diermayr et al 2012). Pacritnib an oral inhibitor has shown better patient tolerability and favourable pharmacokinetics and is currently undergoing phase-II clinical studies against myelofibrosis and lymphoma .…”