 |
 |
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.
In November 2007, Synta announced that it had initiated a global, pivotal Phase
3 clinical trial in patients with metastatic melanoma. In February 2009, the
trial was suspended based on an interim analysis that identified possible
safety concerns. Preliminary results from the trial were presented at ASCO in
May 2009 and Perspectives in Melanoma XIII in October 2009. These results
showed a differential response to treatment with elesclomol based on level of
baseline lactate dehydrogenase (LDH), an established prognostic biomarker in
melanoma and a pre-specified stratification variable in the trial.
Results presented at the NCI-AACR-EORTC meeting in November 2009 demonstrated
that elesclomol binds copper in plasma, facilitating its uptake into cells and
enabling a transition between copper oxidation states inside the cell.
Additional research by Synta and by external collaborators has shown that this
reaction disrupts the metabolic properties of cancer cell mitochondria and
generates the oxidative stress that triggers programmed cell death in cancer
cells. Under normal oxygen conditions elesclomol exhibits potent anti-cancer
activity. Under hypoxic (low oxygen) conditions, which are often associated
with elevated LDH levels, cancer cell metabolism shifts away from the
mitochondria and elesclomol anti-cancer activity is reduced. These results,
together with the results observed in the SYMMETRY trial, suggest excluding
patients with elevated LDH from future trials with elesclomol.
In December 2009, results presented at the American Society for Hematology
showed that elesclomol was highly active against acute myeloid leukemia (AML)
cell lines and primary blast cells from AML patients.
In March 2010, Synta announced that the FDA approved resuming clinical
development with elesclomol.
Plans for future clinical trials with elesclomol will be announced later in
2010.
Elesclomol Presentations
| Meeting/Date
|
Title |
Link |
|
ASH 2009
Annual Meeting of the American Society of Hematology
December 6, 2009 - New Orleans, LA
|
Antileukemic Effects of the Novel Agent Elesclomol.
|
Poster |
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.
|
Poster
|
Perspectives in Melanoma XIII
October 10, 2009 - Baltimore, MD |
SYMMETRYSM Clinical Trial Update
|
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.
|
Presentation |
100th AACR Annual Meeting
April 21, 2009 - Denver, CO |
Elesclomol and chemotherapy agents synergistically
induce apoptosis in breast cancer cells.
|
Poster |
Elesclomol Publications
| Meeting/Date
|
Title |
Link |
Molecular Cancer Therapeutics
August 2008; 7(8): 2319-2327.
|
Elesclomol induces cancer cell apoptosis through
oxidative stress.
|
Publication |
Journal of Clinical Oncology
November 2009; 27(32): 5452-5458.
|
A Phase II, Randomized, Controlled, Double-Blinded
Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV
Metastatic Melanoma.
|
Abstract |
[Top of page]
References
Oxidative Stress and Cancer
-
Fruehauf, J.P., Meyskens, FL: Reactive Oxygen Species: A Breath of Life or
Death? Clinical Cancer Research; 13(3) February 2007, 789-794.
-
Fruehauf, J.P., Trapp, V: Reactive oxygen species: an Achilles' heel of
melanoma? Expert Review of Anticancer Therapy. 8(11) November 2008, 1751-1757.
-
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).
-
Massa, C., et.al.: Enhanced efficacy of tumor cell vaccines transfected with
secretable hsp70. Cancer Res, 2004; 64:1502-1508.
-
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.
-
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].
-
Pelicano, H., et al: ROS stress in cancer cells and therapeutic implications,
Drug Resistance Updates 7 (2004) 97-110.
-
Ramanathan, B., et al: Resistance to Paclitaxel is Proportional to Cellular
Total Antioxidant Capacity, Cancer Research 65: (18), September 2005,
8455-8460.
-
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).
-
Schumacker, P.T.: Reactive oxygen species in cancer cells: Live by the sword,
die by the sword, Cancer Cell, September 2006, 175-176.
[Top of page]
|
|