Dr. Ferrer’s laboratory continues to study the importance of bio-active sphingolipids in human diseases such as cancer and renal injury. Sphingosine-1-phosphate (S1P) is a ubiquitous bioactive lipid that exerts a wide variety of cellular functions via interaction with five G protein-coupled receptors (namely S1PR1-5). Sphingosine kinases (SphK) 1 and 2, which are overexpressed in many pathological conditions including cancer, are the two key enzymes responsible for catalyzing the formation of S1P. The main focus of research work in our lab is to investigate the mechanism and function of SphK2/S1P/S1PR signaling pathways in cancer and in renal inflammation/fibrosis and to develop novel therapeutic strategies targeting S1P pathway based on the forthcoming findings.
Cancer Research: Neuroblastoma (NB), derived from cells of the primitive neural crest, is the most common extra-cranial solid tumor in childhood and the most frequently diagnosed neoplasm during infancy. Despite improvements in outcome for those with low-risk NB, the outcome for children with high-risk NB has improved only modestly. Therefore, novel therapeutic strategies against NB are desperately needed. Our current research work on NB, funded by the NIH grant R01CA168903, mainly focus on three aims: (1) Evaluation of efficacy of immune modulator FTY720 based treatment of NB; (2) Investigating the role of SphK2 and S1P2 on NB tumor growth and progression; (3) Development and testing of S1P2 antagonist JTE-013 analogs with improved anti-cancer properties.
Renal Inflammation/Fibrosis Research: One in 3 American adults are currently at risk for developing kidney disease and the risk increases to 1 in 2 over the course of a lifetime. Ureteropelvic junction obstruction patients (UPJO) have obstructive nephropathy, a condition in which the flow of urine is blocked, is one of the leading causes of chronic kidney disease, resulting in injury/scarring to one or both kidneys. Urinary obstruction is a common cause of acute and chronic renal failure. Little is known about role of S1P pathways in regulating obstructive renal injury, the most common cause of chronic kidney disease in children. Although effective interventions to slow the progression of renal disease have been developed, many patients with chronic kidney disease continue to develop the kidney failure. As progress has stagnated, novel treatment approaches targeting/manipulating the renal scaring mediators with enhanced therapeutic value are clearly needed. Our laboratory has recently discovered that renal injury in mice caused by ureteral obstruction (Unilateral Ureteral Obstruction-UUO model), central to progression of chronic kidney disease is regulated by Sphingosine Kinase2 signaling and can be targeted for therapeutic benefit. Sphingolipid metabolites are emerging as important lipid signaling molecules in both health and disease. Among them, sphingosine 1 phosphate (S1P), produced by phosphorylation of sphingosine by sphingosine kinase 1 and 2 plays important role in number of cellular processes. Therapeutic agents that target other causal and pathophysiological processes of kidney disease hold promise.
Sphingolipid signaling has proven to be a key modulator of inflammatory process. In particular sphingosine kinase-2 (Sphk-2) has been postulated to be a regulator of macrophage polarization. Studies from our lab with SphK-2 knock out mice indicated that the knock out mice had diminishing renal inflammation/ fibrosis in response to unilateral ureteral obstruction, by polarizing the anti inflammatory M2 phenotype macrophages to the injury site. We further continue our studies exploring how SphK2 is involved in molecular pathways leading to M2 macrophage development and polarization. Currently our major interest is to explore Sphingosine kinase-2 inhibitors as renal inflammation/fibrosis modulators. In our preliminary studies we have shown that renal injury was diminished in sphingosine kinase-2 inhibitors treated mice and these mice had reduced inflammatory cell influx and also reduced vascular leak in kidney tissue. We are evaluating the role of sphingosine kinase -2 inhibitors in stabilizing endothelial junctions and diminishing vascular leak in injured kidney.