While I am already running “Rise of the Rune Lords” as a Fantasy Genre adventure in Golorian, I can easily see where the basic plot and most of the story elements would work just as well in other genres – as long as they would accommodate either magic or high-powered psionics.
The adventures would be adaptable for the World of Darkness, Shadowrun, a magic oriented Superhero setting (B.P.R.D. anyone?), or any magic setting on the “real” world by moving the Runelords into an Earth pre-history (or better early history with some research). For example Xin-Shalast could be lost Cibola in the Nevada Desert (Yes, a horrible warping of the “Seven Cities of Gold” myth.)
The AP also works in a Space Opera setting as well. The Runelords become ancient psions (possibly also aliens) who ruled a fallen and now largely forgotten interstellar empire. In “modern times” (from the viewpoint of the characters) Sandpoint would function as a backwater planet, Magnamar becomes the sector capital; even Foxglove can be put on a moon orbiting Magnamar. This works especially well for Space Opera as the characters end up travelling quite a bit through the course of the AP.
Just some thoughts. :D