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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 by disrupting cancer cell
energy production and metabolism.
Preclinical studies have shown that elesclomol acquires copper ions, in the form
of Cu(II), from serum, and, once inside a cancer cell, enables the reduction
reaction Cu(II) to Cu(I). This redox reaction disrupts mitochondrial
respiration in cancer cells and elevates the level of reactive oxygen species
(ROS) beyond sustainable levels. This increase in ROS overwhelms the cancer
cells and ultimately triggers the mitochondrial apoptosis pathway.1,2
This mechanism of action represents a novel way of selectively targeting and
killing cancer cells.
The induction of apoptosis by elesclomol has been observed in a wide variety of
cancer cell types. The anti-cancer activity of elesclomol has also been shown
to require energy metabolism driven primarily through the mitochondria. This
occurs under normoxic (normal oxygen) conditions. Under hypoxic conditions,
often associated with elevated LDH levels, energy production shifts to
glycolysis in the cytoplasm and elesclomol anti-cancer activity is diminished.3
These observations are consistent with findings in a Phase 3 metastatic
melanoma study, where elesclomol activity was observed in subjects with normal
baseline LDH levels, but not in subjects with elevated LDH levels.4
Plans for future clinical trials with elesclomol will be announced later in
2010.
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1 Kirshner JR, He S, Balasubramanyam V, Kepros J, Yang CY, Zhang M,
Du Z, Barsoum J, Bertin J. Elesclomol induces cancer cell apoptosis through
oxidative stress. Molecular Cancer Therapy 2008 Aug; 7(8):2319-27.
2 Nagai M, Vho N, Kostik E, He S, Kepros J, Ogawa LS, Inoue T,
Blackman RK, Wada Y, Barsoum J. The oxidative stress inducer elesclomol
requires copper chelation for its anticancer activity. Molecular Cancer
Therapeutics 2009; 8 (12, suppl 1): Abstract C11. Poster presented at 2009
AACR-NCI-EORTC International Conference on Molecular Targets and Cancer
Therapeutics, Boston, MA
3 Nagai M, Blackman RK, Rao PE, Wada Y, Koya K. Anticancer activity
of elesclomol correlates with low LDH levels and active mitochondrial
respiration. Presented at: American Association for Cancer Research Annual
Meeting, April 2010, Washington DC
4 Hauschild A, Eggermont AM, Jacobson E, O’Day SJ. Phase III,
Randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel
alone in Stage IV Metastatic Melanoma (MM). J Clin Oncol 2009; 27 (18s);
abstract LBA9012. Presented at American Society of Clinical Oncology Annual
Meeting, 2009.
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Elesclomol Presentations
| Meeting/Date
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Title |
Link |
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ASCO Annual Meeting 2010
June 6, 2010 - Chicago, IL
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Phase III, randomized, double-blind study of
elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic
melanoma (MM): 1-year OS update.
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Poster
Abstract |
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101st AACR Annual Meeting
April 20, 2010 - Washington, DC
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Anticancer activity of elesclomol correlates with low
LDH levels and active mitochondrial respiration
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Poster
Abstract |
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101st AACR Annual Meeting
April 20, 2010 - Washington, DC
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Targeting ROS to kill cisplatin-resistant cells
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Poster
Abstract |
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ASH 2009
Annual Meeting of the American Society of Hematology
December 6, 2009 - New Orleans, LA
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Antileukemic Effects of the Novel Agent Elesclomol.
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Poster
Abstract |
AACR-NCI-EORTC
Molecular Targets and Cancer Therapeutics
November 18, 2009 - Boston, MA |
The oxidative stress inducer elesclomol requires
copper chelation for its anticancer activity.
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Poster
Abstract
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Perspectives in Melanoma XIII
October 10, 2009 - Baltimore, MD |
SYMMETRYSM Clinical Trial Update
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Presentation |
ASCO Annual Meeting 2009
May 30, 2009 - Orlando, FL |
Phase 3, randomized, double-blind study of elesclomol
and paclitaxel versus paclitaxel alone in Stage IV metastatic melanoma.
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Abstract |
100th AACR Annual Meeting
April 21, 2009 - Denver, CO |
Elesclomol and chemotherapy agents synergistically
induce apoptosis in breast cancer cells.
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Abstract |
Elesclomol Publications
| Publication/Date
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Title |
Link |
Journal of Clinical Oncology
November 2009; 27(32): 5452-5458.
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A Phase II, Randomized, Controlled, Double-Blinded
Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV
Metastatic Melanoma.
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Abstract |
Breast Cancer Research Treatment
2009 July 16. [Epub ahead of print]
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Elesclomol, counteracted by Akt survival signaling,
enhances the apoptotic effect of chemotherapy drugs in breast cancer cells.
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Publication |
Molecular Cancer Therapeutics
August 2008; 7(8): 2319-2327.
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Elesclomol induces cancer cell apoptosis through
oxidative stress.
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Publication |
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References
Oxidative Stress and Cancer
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Fruehauf, J.P., 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, J.P., 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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O'Day, S., et.al.: A Phase II, Randomized, Controlled, Double-Blinded Trial of
Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV
Metastatic Melanoma. J Clin Oncol. 2009 Oct 13. [Epub ahead of print].
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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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Ramanathan, B., et al: Resistance to Paclitaxel is Proportional to Cellular
Total Antioxidant Capacity, Cancer Research 65: (18), September 2005,
8455-8460.
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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, P.T.: Reactive oxygen species in cancer cells: Live by the sword,
die by the sword, Cancer Cell, September 2006, 175-176.
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