Experimental therapeutics for patients with myeloproliferative neoplasias

Abstract

Philadelphia chromosome (Ph)‐negative myeloproliferative neoplasms (MPNs) are characterized by stem cell‐derived, unrestrained clonal myeloproliferation. The World Health Organization classification system, proposed in 2008, identifies 7 distinct categories of Ph‐negative MPNs including essential thrombocythemia (ET); polycythemia vera (PV); primary myelofibrosis (PMF); mastocytosis; chronic eosinophilic leukemia; chronic neutrophilic leukemia; and MPN, unclassifiable. For many years, the treatment of ET, PV, and PMF, the most frequently diagnosed Ph‐negative MPNs, has been largely supportive. In recent years, that paradigm has been challenged because of the discovery of a recurrent point mutation in the Janus kinase 2 (JAK2) gene (JAK2V617F). This mutation can be detected in the vast majority of patients with PV and approximately half of patients with ET or PMF and serves as both a diagnostic marker as well as representing a putative molecular target for drug development. Several putative targeted agents with significant in vitro JAK2 inhibitory activity and various degrees of JAK2 specificity are currently undergoing clinical evaluation. Furthermore, other investigational non‐tyrosine kinase inhibitor approaches such as immunomodulatory agents and pegylated interferon‐α have also shown promising results in MPNs. Cancer 2011. © 2010 American Cancer Society.

Nuclear JAK2: Form and Function in Cancer

“…In hematologic neoplasms such as chronic myelomonocytic leukemia and acute myeloid leukemia JAK2 is constitutively activated because of a mutation (Levine et al,2005; Baxter et al,2005; Tefferi et al,2005; Bina et al,2010), while aberrant JAK activity due to overexpression of wild‐type JAK2 is also associated with a number of solid tumors, including gastric carcinoma, hepatocellular carcinoma, and head and neck squamous cell carcinoma (Lee et al,2006; Fuke et al,2007; Hedvat et al,2009; Kupferman et al,2009). In different experimental models, tumorigenesis is associated with increased activity of JAK2, and functional ablation of JAK2 protects against the onset of various tumors (Sakamoto et al,2009; He and Zhang,2010; Agrawal et al,2011). Studies in our laboratory showed that wild‐type JAK2 is significantly upregulated in primary gastric cancers, and down‐regulation of JAK2 significantly suppresses the proliferation of gastric cancer cells, suggesting that JAK2 may play a key role in gastric carcinogenesis (Ding et al,2010).…”

Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial

“…Drugs such as hydroxyurea and interferon-alpha have modest activity in controlling splenomegaly and leucocytosis in patients with PMF, and favourable responses to thalidomide and lenalidomide, chiefly in the form of improved haemoglobin and platelet counts, have been reported in a small subset of patients. 31 , 32 Ruxolitinib (a JAK-1/2 inhibitor) was recently approved for the treatment of intermediate and high-risk MF, including PMF, post-PV MF or post-ET MF, with ⩾35 percent reduction in splenic volume in 41.9% of patients, which was maintained for 48 weeks in the majority of patients with such a response. 5 , 33 In the current phase II exploratory trial, only one patient had confirmed disease response (anaemia improvement), whereas most patients had stable disease as best response.…”

Assessing efficacy in myelofibrosis treatment: a focus on JAK inhibition

“…Cytokines and growth factors activate the extracellular portion of their cognate receptors [41,42], which in turn promotes the recruitment of JAK proteins to associate closely with the intracellular portion of these receptors and the activation of the JAK proteins via phosphorylation (Figure 1). Phosphorylation of JAK proteins, in turn, leads to the phosphorylation and activation of several intracellular downstream signaling proteins, such as STAT proteins [42].…”

“…Phosphorylation of JAK proteins, in turn, leads to the phosphorylation and activation of several intracellular downstream signaling proteins, such as STAT proteins [42]. Phosphorylated STATs translocate to the nucleus and act as inducible nuclear-transcription factors [42], which lead to transcriptional modulation and eventual expression of cellular, molecular and (patho)-physiologic actions that were promoted by the initial signal (ligand).…”

“…JAK inhibitors block a catalytic ATP-binding domain within the JAK enzyme, which in turn prevents the phosphorylation of downstream signaling proteins (Figure 1) [41,42]. Importantly, the activity of JAK inhibitors, such as ruxolitinib, is not contingent on JAK2 V617F mutational status [16].…”