Dr. Gutterman’s lab discovered a new family of plant compounds from an Australian desert tree, Acacia Victoriae. These molecules called avicins, have submicromolar pro-apoptotic activity against a range of cancer cells. The avicins are “not so” small organic molecules with a molecular weight of around 2200. They contain a 5 ring core (triterpene) and are decorated by 2 sugars. The pharmacophore is contained in a terpene side chain which contains 2 electrophilic groups. They have concentrated on understanding the effects of avicins on signaling as well as metabolic pathways. Pre-clinical studies demonstrate favorable parenteral pharmacology, anti-tumor activity, as well as acceptable toxicity in rodents and dogs. FDA has approved avicins for Phase 1-2 clinical testing in solid tumors and hematologic malignancies, which are expected to commence in 2013-14.
In short, the avicins induce a reprogramming of a variety of cancer cells, suppressing both glycolysis as well as critical mitochondrial function (O2 consumption, Kreb’s cycle metabolites). Most growth promoting, anabolic, and proliferative pathways are suppressed including mTOR, cMyc, STAT-3. In addition, avicins suppress EMT and inhibit mammosphere and prostate sphere formation. Cancer stem cell transcriptional pathways such as snail and twist are suppressed.
Continued work is focused on identifying critical molecular pathways regulated in cancer cells by avicins. In addition, tumor resistance pathways are also being studied. Studies are also being done in two strains of yeast, which have often been used to help narrow down the target space. In an attempt to understand the mechanism we are collaborating extensively with other institutions. Biocomputational analysis of the NC! 60 cell screen as well as combination in vitro studies suggest avicins have a unique mechanism of action not shared by any known anti-cancer compound. Several semi-synthetic second generation compounds are also being generated and studied.