Novel therapies for myelofibrosis

Abstract

Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2V617F mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e., mammalian target of rapamycin/AKT/phosphoinositide 3-kinase,) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies.

Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis

“…In light of its limited hematologic toxicity and its efficacy in myelofibrosis symptom relief, INCB039110 may be useful in the future as part of combination therapy with agents that have complementary activity or dose-limiting hematologic toxicities, such as Hedgehog pathway inhibitors (e.g., sonidegib), phosphatidylinositol 3-kinase inhibitors, histone deacetylase inhibitors (e.g., panobinostat), and hypomethylating agents (e.g., 5-azacytidine). 22,23 Combinations involving selective JAK1 inhibition instead of JAK1/JAK2 inhibition may offer the potential for similar efficacy with less myelosuppression, although this has not been confirmed in clinical trials.…”

Overview of the Mutational Landscape in Primary Myelofibrosis and Advances in Novel Therapeutics

“…IRAK1 is overexpressed in both myelodysplastic syndromes and Fanconi anemia, which display markedly deregulated hematopoiesis (Hofmann et al, 2002;Pellagatti et al, 2010). Phase I studies showed minimal myelosuppression, and in results from a phase 2 study with 35 patients, gastrointestinal side effects were most common, notably diarrhea (Komrokji et al, 2015;Jain and Mesa, 2016 Improved activity compared to JAK inhibition alone (Stein et al, 2015). Ruxolitinib combined with buparlisib is being evaluated (NCT01730248) Panobinostat with ruxolitinib showed >50% reduction in splenomegaly in 79% of patients, with 100% reduction in 53% (Kiladjian et al, 2014).…”

“…Secondly, JAK inhibitors are unable to eradicate the mutant JAK. Furthermore, they do not selectively target mutant JAK2 alone, potentially leading to adverse effects including cytopenias that result from disruption of normal JAK signaling (Stein et al, 2015). Impaired dendritic cell function resulting from JAK1/JAK 2 inhibition can increase susceptibility to infection, while blockade of FLT3 can cause diarrhea (Heine et al, 2013).…”

“…In the long-term, JAK/STAT activation can persist despite the use of JAK inhibitors via the formation of heterogenous dimers with other JAK proteins (Koppikar et al, 2012). Finally, the pathogenesis of PMF involves molecular abnormalities at multiple levels which may not all be targeted by a single agent (Stein et al, 2015). This was demonstrated in an in vivo study which showed that resistance to JAK inhibitors can arise via the activation of PDGF-mediated MAPK signaling pathways independent of JAK blockade (Meyer et al, 2017).…”

“…PU-H71 is an Hsp-90 inhibitor that regulates JAK2 expression and thus reduces activation of downstream pathways including STAT3/5, resulting in cell death in both MPL and JAK-mutant clones (Santos and Verstovsek, 2013). In a separate study, another HSP-90 inhibitor, AUY922 decreased mutant JAK expression and increased apoptosis of CD34+ cells (Fiskus et al, 2011;Stein et al, 2015). Ganetespib, another HSP-90 inhibitor, decreased in vitro and in vivo STAT activity (Proia et al, 2011).…”