Elesclomol (formerly STA-4783) induces oxidative stress selectively in cancer cells and inhibits tumor growth independent of immune status
Authors: John Bertin, Irma Allen, Vish Balasubramanyam, Kwan Chan, Zhenjian Du, Suqin He, Amy Hutchings, Takayo Inoue, Jane Kepros, Jessica Kirshner, Timothy Korbut, Robert Mihalek, Patricia Rao, Jim Sang, Don Smith, Noriaki Tatsuta, Chin-Yu Yang, Chaohua Zhang, Haili Zhang, Mei Zhang, Dan Zhou, James Barsoum, Kevin Foley
Journal: Cancer Research (2008)

3300  Background: Elesclomol (formerly STA-4783) is a novel, small molecule investigational drug candidate that stimulates production of reactive oxygen species (ROS) and preferentially induces apoptosis in cancer versus normal cells. In a double-blind, randomized and controlled multi-center Phase 2 trial in patients with stage IV metastatic melanoma, treatment with elesclomol plus paclitaxel doubled median progression-free survival relative to treatment with paclitaxel alone, with a safety profile comparable to paclitaxel. Elesclomol was granted Fast Track status and a pivotal Phase 3 trial in metastatic melanoma is underway (SYMMETRYSM). Results: Transcriptional profiling was performed on human Hs294T melanoma and Ramos lymphoma cell lines treated with either 100 nM elesclomol or 250-500 nM paclitaxel for 6 hours. Elesclomol, but not paclitaxel, induced a classic oxidative stress response characterized by increased expression of ROS-regulated genes such as HSP70, metallothioneins and antioxidants. ROS was induced by elesclomol 1 hr after treatment, followed by induction of HSP70 at 1-3 hrs. Sustained ROS production resulted in activation of the intrinsic mitochondrial apoptotic pathway as demonstrated by mitochondrial membrane depolarization and cardiolipin oxidation at 3-6 hrs, followed by cytochrome c release and caspase-9 activation at >6 hrs. We have previously shown that elesclomol inhibited tumor growth as a single agent and enhanced paclitaxel in syngeneic tumor models conducted in wild-type mice. Since HSP70 protein has been reported to activate the immune system, we examined synergy between elesclomol and paclitaxel in T cell-deficient (nu/nu), B/T cell-deficient (SCID, Rag2 knockout), and B/T/NK cell-deficient (SCID-Beige, Beige-nu/nu-Xid) mouse strains implanted with the human M14 melanoma cell line. In each case, elesclomol synergized with paclitaxel and caused tumor regressions. Similarly, elesclomol was found to enhance the activity of gemcitabine in immunodeficient mice. Conclusions: Our results demonstrate that elesclomol, but not paclitaxel, induced a classic oxidative stress response in tumor cells, and that sustained ROS production led to activation of the intrinsic mitochondrial apoptotic pathway. Furthermore, elesclomol enhanced the activity of both paclitaxel and gemcitabine independent of immune status in mouse xenograft tumor models. Cancer cells produce increased ROS relative to normal cells, and hence exist in a state of elevated oxidative stress. Cancer cells are therefore susceptible to insults that further increase ROS levels, thus pushing the cancer cell beyond its tolerability limit for oxidative stress and leading to apoptosis. In this way, elesclomol takes advantage of a fundamental hallmark of cancer in order to chemosensitize and selectively kill cancer cells, with little effect on normal cells.