br PI K Akt mTOR

PI3K/Akt/mTOR Pathway Inhibition A number of agents that target various nodes of the phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, including PI3K and mTOR inhibitors, are currently in development for the treatment of MPNs. This pathway is a crucial regulator of cell growth, survival, and metabolism conditions (Saleiro and Platanias, 2014; Mohindra et al., 2014). It mediates ribosomal translation of mRNA, via downstream effectors 4EBP1 and S6K, into proteins required for cell growth, cycle progression, and metabolism. The overactivation of this pathway, which can be result from constitutive activity of upstream JAK2 (Fig. 1), has been observed in MPNs, and its various roles in the pathogenesis of MPNs has been reviewed in detail elsewhere (Bartalucci et al., 2013a; Pandey and Kapur, 2015; Mclornan and Harrison, 2013). In brief, the PI3K/Akt/mTOR pathway may mediate disease progression as well as cellular drug resistance. The rapalog mTOR inhibitor everolimus, currently approved for the treatment of various advanced solid tumors, was shown to have clinical activity in MF in a phase 1/2 clinical trial (Guglielmelli et al., 2011). Of 30 evaluable high/intermediate-risk MF patients who had received prior therapy, splenomegaly reduction of >50% and >30% occurred in 20% and 44%, respectively, and 69% and 80% experienced complete resolution of constitutional symptoms, respectively. The responses were not associated with a reduced JAK2 V617F allele burden or with cytokine levels. Grade 1/2 stomatitis was the most common toxicity, occurring in the majority of subjects. Of great clinical interest, based on the results of multiple preclinical studies, is the combination of PI3K/Akt/mTOR inhibitors with JAK inhibitors (Choong et al., 2013; Bartalucci et al., 2013b; Szymańska et al., 2015). In a cellular screening assay, synergistic anti-proliferative activity was observed in JAK2-mutated MPN mouse Ba/F3 gtpase inhibitor when subjected to combinations of various pan-class I PI3K inhibitors and JAK inhibitors (Choong et al., 2013). Moreover, in murine MPN models, the PI3K/JAK inhibitor doublets synergistically improved survival and delayed onset of splenomegaly (Choong et al., 2013). The use of BEZ235, a dual PI3K/mTOR inhibitor, alone or in combination with ruxolitinib, in in vitro and in vivo preclinical models of JAK2 V617F-mutated MPN, also led to synergism (Bartalucci et al., 2013b). Other classes of agents of interest include the catalytic mTORC1/2 inhibitors and AKT inhibitors. Currently, a number of clinical trials involving the use of PI3K/AKT/mTOR inhibitors alone or in combination are in progress (NCT01730248 and NCT02493530).
Telomerase Inhibition Telomeres, which are nucleoproteins located at the ends of chromosomes, maintain genome stability by protecting the ends of chromosomes from degradation (Ouellette et al., 2011). Many neoplastic cells are able to obviate this replicative senescence by activating telomerase, a reverse transcriptase that maintains telomere length by adding nucleotides to the telomere during cell division. Telomerase inhibition has been demonstrated to induce this process among neoplastic cells (Ouellette et al., 2011). Imetelstat, an intravenously administered, 13-mer lipid-conjugated antisense oligonucleotide that targets the RNA template component of telomerase, conferred an 89% overall response rate in a phase 2 study of 18 ET patients for whom first-line therapy had failed (Baerlocher et al., 2015). Ten of the patients received therapy for a median of 17months, and among the 8 patients with JAK2 V617F mutations, molecular responses were noted in 7. In a pilot study involving 33 MF patients, half of whom had received prior JAK inhibitor therapy, 21% attained a complete (n=4) or partial remission (n=7; CR, PR) of a median duration of 18 and 10months, respectively (Tefferi et al., 2015). Response rates were higher among those with wild-type ASXL1, as compared to mutated ASXL1 (32% versus 0%, P=0.07), and among those with a mutation in SF3B1 or U2AF1, as compared with their wild-type counterparts (38% versus 4%, P=0.04). Among the CR patients, bone marrow fibrosis reversal and molecular responses were noted in 100% and 75%, respectively. Baseline telomere length was not predictive of response. In both of these studies, grade 3/4 cytopenias occurred in approximately 10–30% of patients, and many of the patients had low-grade liver function test abnormalities. In addition to antisense oligonucleotide strategies, the use of telomerase-targeting small molecules and immunotherapy represent potential strategies (Mocellin et al., 2013).