Published online Sep 7, 2014. doi: 10.3748/wjg.v20.i33.11700
Revised: March 21, 2014
Accepted: June 2, 2014
Published online: September 7, 2014
Malignant peritoneal mesothelioma (PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be suggested by occupational exposure history, but ultimately relies heavily on imaging and diagnostic biopsy. Early treatment options including palliative operative debulking, intraperitoneal chemotherapy, and systemic chemotherapy have marginally improved the natural course of the disease with median survival being approximately one year. The advent of cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has dramatically improved survival outcomes with wide median survival estimates between 2.5 to 9 years; these studies however remain largely heterogeneous, with differing study populations, tumor biology, and specific treatment regimens. More recent investigations have explored extent of cytoreduction, repeated operative intervention, and choice of chemotherapy but have been unable to offer definitive conclusions. CRS and HIPEC remain morbid procedures with complication rates ranging between 30% to 46% in larger series. Accordingly, an increasing interest in identifying molecular targets and developing targeted therapies is emerging. Among such novel targets is sphingosine kinase 1 (SphK1) which regulates the production of sphingosine-1-phosphate, a biologically active lipid implicated in various cancers including malignant mesothelioma. The known action of specific SphK inhibitors may warrant further exploration in peritoneal disease.
Core tip: Peritoneal mesothelioma (PM) historically has been associated with a very poor prognosis. Cytoreduction with hyperthermic intraperitoneal chemotherapy improved survival outcomes but carries significant morbidity. Increasingly, research has focused on identifying molecular targets and only a handful have been described; even fewer directed therapies have been evaluated. We review the role of sphingosine kinase 1 and sphingosine-1-phosphate (S1P) signaling in PM and discuss the possibility of targeting it with FTY720, a functional antagonist of S1P Receptor 1. Further investigation is warranted in this new avenue of interest.