Marine Sponge leads Researchers to Anti-Tumor Compound
Researchers have discovered the mammalian counterpart to a previously discovered glycosphingolipid derived from a sea sponge that, in an amazing coincidence of nature, activates natural killer (NK) T cells, which play a key role in helping the immune system fight cancer.
"It is remarkable that this marine sponge contains within it antitumor properties, a product that has such an impact on vertebrates," says Albert Bendelac, Ph.D., Professor, Department of Pathology, whose research was published in the December 3, 2004, issue of Science. "This sponge glycolipid doesn't occur in mammals, but it provided us with a guide to find similar natural activators for the NKT cells in humans, which we have done."
The first known substance to fully activate NKT cells, alpha-galactosylceramide, the glycosphingolipid derived from an Okinawan sea sponge Agelas mauritianus, was discovered to trigger an anti-tumor response in mice. This discovery led researchers towards the identification of the mammalian counterpart. Dapeng Zhou, Ph.D., postdoctoral fellow in the Bendelac lab, first isolated a key family of proteins called saposins in collaboration with researchers from Scripps Research Institute and Brigham Young University and then focused his efforts on known targets for these saposins, which included the natural ligand iGb3.
The discovery of iGb3 will allow researchers to explore how this compound is produced in some, but not all, tumors and may help explain why some tumors are more susceptible and others are resistant to attack by the immune system.
"Until now we had no idea what activated NKT cells, except for one curious compound, this marine sponge glycosphingolipid," Bendelac continues. "Our work has centered on learning more about this compound, working to find the naturally occurring mammalian counterpart and translating that into viable treatment options."
A purified synthetic version derived from the marine sponge glycolipid, a-GalCer or KRN 7000, is now in phase-2 human clinical trials. However, use of a-GalCer has been associated with NKT cell overstimulation, which leads to a rapid burst of activity and secretion of interferon-gamma. Essentially, the NKT cells activated by this compound fizzle and disappear from the body within a short amount of time.
"We are hoping that iGb3 will prove more useful than the synthetic version of the marine sponge glycolipid because there is an element of natural selection involved in its occurrence," concludes Bendelac. "The bottom line is that this naturally occurring element provides us with a great deal of information as we try to understand tumor creation and immune responses within the human body."
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