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BM niche dysregulation in MPN
ity and ECM components; however, a phase-II study in MF failed to show significant clinical benefits.106 A study with a monoclonal antibody against TGF-β (fresolimum- ab) is currently ongoing in MF, although preliminary results have not described any relevant changes in fibrosis.107 Finally, an inhibitor of the TGF-β receptor-I- kinase, galunisertib (LY2157299) has been shown to induce reductions in fibrosis in MPN murine models.108 Monoclonal antibodies against LOL-2 (simtuzumab) have been tested either as monotherapy or in combination with ruxolitinib in a phase-II study with overall limited efficacy in MF,109 despite the promising in vitro results. Hypomethylating agents such as azacitidine (5-Aza) and decitabine have been investigated in high-risk MF patients and accelerated/blastic phases of the disease. A combined clinical trial with ruxolitinib and 5-Aza is currently ongo- ing and recent published results have demonstrated mar- row fibrosis reductions in 57% of the total cohort (31 cases) at 24 months in addition to acceptable spleen responses.110 Further research is required to determinate the impact of these hypomethylating agents, with partic- ular attention to the MPN marrow niche.
Therapeutic modulation of the neuro-HSC niche in MPN, introduced above, has recently been explored. Drexler et al. report on a phase II trial of an oral β-3 adren- ergic agonist (mirabegron) in 39 patients, many of whom had a long duration of disease, with a JAK2 V617F-mutat- ed MPN who underwent treatment for up to six months. BM core analysis in 20 of the enrolled patients showed increases in Nestin+ BMSC in a proportion of patients (but not in those also receiving hydroxycarbamide); several showed mild reductions in fibrosis and modulation of the characteristic megakaryocyte clustering.111,112 Although the study end points of a >50% reduction in JAK2 allelic bur- den or sustained reductions in splenomegaly were not reached, these intriguing data highlight the potential ther- apeutic avenues of targeting this neuro-HSC axis in MPN.
With regard to aberrant upregulation of cytokines in MPN, ruxolitinib and other JAKi have been shown to decrease levels of many pro-inflammatory cytokines, including both VEGF and PDGF, as discussed above.69 The Myeloproliferative Disorders Research Consortium con- ducted a phase II trial of the anti-VEGF agent (bevacizum- ab) in 13 patients, 11 of whom were evaluable, to assess if a potential disease modification could be achieved. The
dosing strategy was 15 mg/kg intravenously every 21 days; none of the patients demonstrated significant bene- fits. This lack of response coupled with toxicity led to the premature closure of the study; the authors commented that different dosing strategies may be required.113 Other drugs have been developed to target VEGF-receptors, like the tyrosine kinase inhibitor vatalanib, but with modest results.114 Lastly, control or regulation of the marrow hypoxia status could be a potential goal in the manage- ment of MPN in view of the key role of oxygen regulation pathways in the pathogenesis and maintenance of these disorders. HIF-1α is essential for HSC maintenance, as dis- cussed. However, in the MPN environment, it participates in both angiogenesis and promotion of suppressor genes, aiding clonal cell adaptation to a hypoxic environ- ment.115,116 Therefore, targeting HIF1-α has been explored in recent years in both solid and non-solid cancers.117 Bortezomib, a proteasome inhibitor extensively used in plasma cell dyscrasias, indirectly inhibits HIF-1α in MF patients as demonstrated by Barosi et al.118 Although, to date, few published studies have focused on targeting hypoxia and HIF-pathways in MPN, it remains an attrac- tive area of research.
Conclusions
As our knowledge expands, the complex and dynamic structure of the bone marrow niche in both health and dis- ease is being constantly refined. It is apparent that, in MPN, the mutated-HSC disrupts the harmony of the bone mar- row niche, promoting a self-reinforcing environment that facilities their proliferation at the expense of normal hematopoiesis. Furthermore, the MPN-niche can confer therapeutic resistance and potentiate disease progression towards blastic phase disease. Besides the potentially cura- tive procedure of allogeneic stem cell transplantation, attempts to target various components of the MPN-niche have led to variable results and often a lack of sustained clinical benefit. Given the complexity, it is, therefore, increasingly apparent that combinatorial or sequenced ther- apeutic strategies will be required. As our appraisal of niche dysregulation grows, and we learn more from the current therapeutic trials discussed above, more rational niche-tar- geted treatment strategies will ultimately be developed.
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