is a first-in-class mitochondrial metabolism inhibitor that exerts
potent anti-cancer activity through targeting the electron transport
chain in mitochondria. Elesclomol is currently being studied as a single
agent in a Phase 1 trial in acute myeloid leukemia and a Phase 2 trial
in combination with paclitaxel in ovarian cancer sponsored by the
“In three randomized trials, once-weekly dosing of elesclomol in
combination with paclitaxel has demonstrated clear evidence of activity
in patients with low lactate dehydrogenase (LDH),” said
In vitro results demonstrated that elesclomol causes specific and preferential accumulation of copper in cancer cell mitochondria, thereby increasing levels of mitochondrial reactive oxygen species (ROS) in tumor cells ultimately leading to apoptosis (programmed cell death). In contrast, treatment with elesclomol did not result in copper accumulation or apoptosis in normal blood cells.
“Our improved understanding of the mechanism of action of elesclomol and identification of biomarkers for selection of patients that are most likely to benefit from elesclomol treatment suggests potentially wide application in a range of human cancers. Today’s presentation points to a path forward in clinical development of elesclomol both as a single agent as well as in combination with other anti-cancer agents,” concluded Dr. Vukovic.
Continuous elesclomol infusion results in enhanced single agent antitumor efficacy
Title: Cancer-selective mitochondrial copper transport by elesclomol results in potent single agent efficacy in multiple tumor types.
Permanent Abstract Number: C168
Elesclomol is a first-in-class, investigational drug candidate that triggers programmed cell death (apoptosis) in cancer cells through a novel mechanism: selectively targeting the electron transport chain in cancer cell mitochondria, disrupting cancer cell energy metabolism.
Elesclomol binds copper in plasma, which causes a change in conformation that enables its uptake through membranes and into cells. Elesclomol binds copper in an oxidative, positively charged, state called Cu(II). Once inside mitochondria, an interaction with the electron transport chain reduces the copper from Cu(II) to Cu(I), resulting in a cascade of redox reactions, a rapid increase of oxidative stress, disruption of mitochondrial energy production, and the initiation of the mitochondrial apoptosis pathway.
Mitochondria generate energy for cells, but also can induce apoptosis under certain conditions, such as a high level of oxidative stress. By sensitizing mitochondria and reducing barriers to apoptosis, elesclomol may provide a means to overcome resistance to traditional chemotherapy or targeted therapy.
Cancer cell mitochondria can be selectively targeted by elesclomol because cancer cell mitochondria are structurally and functionally different from their normal counterparts, making them more susceptible to changes to mitochondrial metabolism.
Safe Harbor Statement
This media release may contain forward-looking statements about
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125