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Program Overview
About Elesclomol
Elesclomol is a first-in-class, investigational drug candidate that triggers
apoptosis (programmed cell death) in cancer cells. Cancer cells operate at high
levels of reactive oxygen species (ROS), or oxidative stress. Elesclomol is
believed to act by increasing the level of oxidative stress in cancer cells
even further, beyond sustainable levels, inducing apoptosis. This mechanism of
action, called oxidative stress induction, represents a novel way of
selectively targeting and killing cancer cells.
In preclinical models elesclomol showed potent anti-cancer activity against a
broad range of cancer cell types, as well as an ability to enhance the efficacy
of certain chemotherapy agents with minimal additional toxicity. Cancers with
elevated levels of reactive oxygen species (ROS) may be the most vulnerable to
the oxidative stress induction mechanism of elesclomol. Tumor types with high
ROS include melanoma, prostate, breast, ovarian, pancreatic, hematologic, and
others.
In a 21-center, double-blind, randomized, controlled Phase 2b clinical trial in
81 patients with metastatic melanoma, elesclomol in combination with paclitaxel
met the primary endpoint – doubling the median time patients survived without
their disease progressing – compared to paclitaxel alone (p= 0.035).
In November 2007, Synta announced that it had initiated a global, pivotal Phase
3 clinical trial ( SYMMETRYSM) in patients with metastatic melanoma,
with the same design as the Phase 2b trial. In February 2009, following a
review of the independent Data Monitoring Committee that identified possible
safety concerns, Synta suspended the SYMMETRY trial as well as other ongoing
trials of elesclomol pending further analysis of results. Preliminary results
from the SYMMETRY trial were presented at ASCO 2009 in Orlando, Florida.
Additional analyses are ongoing, and are expected to be presented later in 2009
or early 2010.
Elesclomol Mechanism of Action
Elesclomol's mechanism of action, oxidative stress induction, has broad
potential as a new category of anti-cancer therapy.
In a series of in vitro and in vivo experiments, elesclomol has
been shown to rapidly cause an increase in oxidative stress – the level of ROS
– inside cancer cells (click here for the publication). This increase in ROS is
observed through the measurement of levels of individual reactive oxygen
species, such as hydrogen peroxide, directly; or through measuring the
increased expression of genes that are induced by the presence of high levels
of ROS, including stress proteins such as heat shock protein 70 (Hsp70).
The elevation of ROS inside cancer cells causes a measurable shift in the
balance of pro- and anti-apoptotic factors in the cell, including an increase
in Bax, a decrease in Bcl-2, and the opening of the mitochondrial pores that
allow release of Cytochrome C. These changes make cancer cells more likely to
undergo apoptosis and lead to two effects observed in vitro and in vivo: (1)
direct apoptosis induction by elesclomol as a single agent, and (2) enhancement
of activity of other agents, such as chemotherapies, that act through the
intrinsic mitochondrial apoptosis pathway.
Elesclomol-ROS - apoptosis pathway
Presentations
References
Oxidative Stress and Cancer
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B Ramanathan et al: Resistance to Paclitaxel is Proportional to Cellular
Total Antioxidant Capacity, Cancer Research 65: (18), September 2005,
8455-8460.
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Fruehauf, JP, Meyskens, FL: Reactive Oxygen Species: A Breath of Life or Death?
Clinical Cancer Research; 13(3) February 2007, 789-794.
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Fruehauf, JP, Trapp, V: Reactive oxygen species: an Achilles' heel of melanoma?
Expert Review of Anticancer Therapy. 8(11) November 2008, 1751-1757.
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Gastpar, R., Gehrmann, M., et.al.: Heat shock protein 70 surface-positive tumor
exosomes stimulate migratory and cytolytic activity of natural killer cells.
Cancer Res, 2005; 65 (12).
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Massa, C., et.al.: Enhanced efficacy of tumor cell vaccines transfected with
secretable hsp70. Cancer Res, 2004; 64:1502-1508.
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Noessner, E., et.al.: Tumor-derived heat shock protein 70 peptide complexes are
cross-presented by human dendritic cells. J of Immunology, 2002; 169:5424-5432.
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Pelicano, H et al: ROS stress in cancer cells and therapeutic implications,
Drug Resistance Updates 7 (2004) 97-110.
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Schmitt, E., et.al.: Intracellular and extracellular functions of heat shock
proteins: repercussions in cancer therapy. J of Leukocyte Biology, 2007; Vol 81
(published as DOI 10.1189/jlb.0306167, Aug 2006).
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Schumacker, PT: Reactive oxygen species in cancer cells: Live by the sword, die
by the sword, Cancer Cell, September 2006, 175-176.
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