Ruxolitinib significantly enhances in vitro apoptosis in Hodgkin lymphoma and primary mediastinal B-cell lymphoma and survival in a lymphoma xenograft murine model

Abstract

Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) share similar molecular features by gene expression profiling. Frequent gains of chromosome 9p exhibit higher Janus Kinase 2 (JAK2) transcript levels with increased JAK2 activity, suggesting aberrant activity of JAK2 and STAT pathways. This signaling pathway alteration may in part play an important role in the pathogenesis and/or chemoradiotherapy resistance in HL and PMBL. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor, with activity against myeloproliferative neoplasms (MPNs) including those harboring the JAK2V617F mutation. We investigated the in vitro and in vivo efficacy of ruxolitinib and changes in downstream signaling pathways in HL and PMBL. We demonstrated that ruxolitinib significantly inhibited STAT signaling in both HL and PMBL with constitutively active JAK2 signaling. We also observed that ruxolitinib significantly induced in vitro anti-proliferative effects (p < 0.05) and increased programmed cell death (p < 0.05) against both HL and PMBL cells. Importantly, ruxolitinib significantly inhibited tumor progression by bioluminescence (p < 0.05) and significantly improved survival in HL (p = 0.0001) and PMBL (p < 0.0001) xenograft NSG mice. Taken altogether, these studies suggest that ruxolitinib may be a potential adjuvant targeted agent in the therapeutic approach in patients with high risk HL and PMBL.

Inhibition of tumor growth and angiogenesis of tamoxifen‑resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor

“…CAM, chorioallantoic membrane; VEGF, vascular endothelial growth factor; sqPCR, semi-quantitative polymerase chain reaction; TAMR, tamoxifen resistant. improve survival in HL and PMBL xenograft mice (47). In the current study, we showed for the first time that STAT3 activity was highly increased in TAMR-MCF-7 cells, and that ruxolitinib inhibited cell proliferation and tumor growth in TAM-resistant breast cancer cells, though the inhibition intensity is marginal.…”

“…Among these, tofacitinib (Xeljanz) and ruxolitinib have been approved for the treatment of rheumatoid arthritis, myelofibrosis, and polycythemia vera (PCV), and are now in clinical trials for novel therapeutic applications, such as colitis and various solid tumors (pancreatic cancer, breast cancer, and non-small-cell lung cancer (NSCLC) (45). It has been reported that ruxolitinib suppresses Hodgkin's lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) growth in vitro, and increases programmed cell death against lymphoma cells (47). Ruxolitinib has also been shown to significantly inhibit tumor growth and The control CAM of a 10-day-old chick embryo was exposed to PBS.…”

Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma

“…amplification [14]. The anti-tumor effect of ruxolitinib was also demonstrated in both HL and PMBL cells and xenograft models [15]. Although this discrepancy of previous pre-clinical studies with the results of our study could not be clearly explained, the influence of JAK2 signaling on the growth of tumor cells in human might be different from in vitro and in vivo models, and this might be related with different outcome of ruxolitinib in HL and PMBCL of this pilot study.…”

Advances in targeted therapy for malignant lymphoma

“…Ruxolitinib significantly enhanced apoptosis in HL and PMBCL in vitro and promoted survival in a lymphoma xenograft murine model. 244 A phase 2 study (NCT01877005) of ruxolitinib in advanced relapsed or refractory HL showed poor efficacy as monotherapy (ORR 9.4% and CR 0%). 245 Ruxolitinib and navitoclax, a Bcl-2/Bcl-XL inhibitor, reduced the tumor burden and prolonged survival in an ATLL xenograft murine model.…”