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ELESCLOMOL
Mitochondria Metabolism Inhibitor

Program Overview | Clinical Trials |  Presentations & Publications |  References

Program Overview

About Elesclomol

Elesclomol is a first-in-class, investigational drug candidate that triggers programmed cell death (apoptosis), in cancer cells through a novel mechanism: disrupting cancer cell energy metabolism by selectively targeting the electron transport chain in cancer cell mitochondria.

Upon infusion, elesclomol binds copper in plasma, causing 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, the elesclomol-Cu(II) complex interacts with the energy production mechanism of the cell, or the electron transport chain. This interaction reduces the copper from Cu(II) to Cu(I), resulting in a cascade of reduction-oxidation, or redox, reactions, that causes a rapid increase of oxidative stress, disruption of mitochondrial energy production, and ultimately, triggering of the mitochondrial apoptosis pathway.

Mitochondria generate energy for cells, but also can drive apoptosis under certain conditions, such as a high level of oxidative stress. By increasing oxidative stress inside mitochondria and inducing apoptosis, elesclomol may provide a means to overcome resistance to traditional chemotherapy or targeted therapy. Elesclomol has shown potent cancer-cell killing activity against a broad range of cancers in vitro, and synergistic anti-cancer activity with paclitaxel and other agents in animal models of cancer.

LDH: predictive biomarker for activity

LDH is an enzyme that plays a key role in cancer cell energy metabolism. Under normal oxygen, or normoxic, conditions, energy in tumors is primarily generated by conversion of nutrients to adenosine triphosphate, or ATP, in the mitochondria, with oxygen as a key component of this process. Levels of LDH generally remain in the normal range in this state. Under low oxygen, or hypoxic conditions, energy in tumors is primarily generated by glycolysis in the cytoplasm, and levels of LDH may increase. Accordingly, LDH can be used as a marker of mitochondrial activity, or tumor cell metabolic state.

Elesclomol kills cancer cells in which the mitochondrial ETC is the dominant source of energy production. This occurs under normal oxygen (normoxic) conditions. When cells are under low oxygen (hypoxic) conditions, energy production shifts to glycolysis in the cytoplasm, producing energy from the conversion of glucose into other byproducts; mitochondrial energy production is reduced or absent. Under these conditions, elesclomol loses anti-cancer activity.

Glycolysis under hypoxic conditions is reflected in an increase in the levels of the enzyme lactate deyhdrogenase (LDH). This suggests that level of LDH may be a predictive biomarker for elesclomol activity. Evidence that elesclomol anti-cancer activity correlates with metabolic state – oxygen conditions and level of LDH – includes:

  • elesclomol shows potent activity, with IC50<10 nM in over 150 different cancer lines, against cells grown under normal oxygen conditions, but little to no activity against cells grown under hypoxic conditions;
  • elesclomol shows little to no activity against cells treated with CoCl2, a chemical mimetic of hypoxia;
  • treating hypoxic cells with the LDH inhibitor oxamate, which induces a shift from glycolysis back to mitochondria-driven oxidative phosphorylation, restores elesclomol anti-cancer activity; and
  • within the same cancer type, elesclomol is less active in cell lines with high levels of HIF1a (hypoxia inducible factor 1 alpha) and LDH, markers of hypoxic conditions; and more active in cells with low levels of HIF1a and LDH.

Clinical observations have been consistent with the preclinical findings that elesclomol activity depends on metabolic state at the cellular level. In three randomized trials, in a total of over 800 patients, elesclomol showed clinical activity that correlated with baseline level of LDH. Benefit was seen only in patients with the low to normal levels of LDH associated with normoxic conditions. In our ongoing and planned studies with elesclomol, we anticipate enrolling only patients with low to normal LDH levels, as these are the patients we believe are most likely to derive benefit from treatment with elesclomol.

Clinical Trials

Phase 2 in Combination with Paclitaxel in Ovarian Cancer

This Phase 2 single-arm, open-label study will recruit up to approximately 50 patients who have progressed on platinum-based therapy. The primary objectives of the trial are to assess activity, based on objective response rate, and safety of the combination in this patient population. Secondary objectives include assessing progression-free survival and overall survival. Elesclomol sodium 200 mg/m2 and paclitaxel 80 mg/m2 will be given as separate 1 hour IV infusions weekly for three weeks followed by one week rest, comprising a four-week cycle. Treatment may continue until disease progression. Click here for further information.

Phase 1 Trial in Acute Myeloid Leukemia (AML)

This is a Phase 1 dose-escalation study of elesclomol sodium in patients with relapsed or refractory acute myeloid leukemia (AML). The primary objectives of study are to characterize safety, tolerability, and pharmacokinetics. Additional objectives are to identify the phase 2 dose and characterize signs of biologic and clinical activity. Click here for more information on this trial.

Elesclomol Presentations

Meeting/Date Title Link

AACR-EORTC-NCI Molecular Targets and Cancer Therapeutics Conference
November 15, 2011 - San Francisco, CA

Cancer-selective mitochondrial copper transport by elesclomol results in potent single agent efficacy in multiple tumor types. Poster

Abstract

102nd AACR Annual Meeting
April 4, 2011 - Orlando, FL

Elesclomol-Cu chelate selectively targets mitochondria to induce oxidative stress. Poster

Abstract

102nd AACR Annual Meeting
April 4, 2011 - Orlando, FL

Downregulation of thioredoxin-1 confers resistance to cisplatin and sensitivity to the ROS generating agent elesclomol.. Poster

Abstract

ASCO Annual Meeting 2010
June 6, 2010 - Chicago, IL

Phase III, randomized, double-blind study of elesclomol and paclitaxel versus paclitaxel alone in stage IV metastatic melanoma (MM): 1-year OS update. Poster

Abstract

101st AACR Annual Meeting
April 20, 2010 - Washington, DC

Anticancer activity of elesclomol correlates with low LDH levels and active mitochondrial respiration Poster

Abstract

101st AACR Annual Meeting
April 20, 2010 - Washington, DC

Targeting ROS to kill cisplatin-resistant cells Poster

Abstract

ASH 2009
Annual Meeting of the American Society of Hematology
December 6, 2009 - New Orleans, LA

Antileukemic Effects of the Novel Agent Elesclomol. 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. Poster

Abstract
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

Abstract
100th AACR Annual Meeting
April 21, 2009 - Denver, CO
Elesclomol and chemotherapy agents synergistically induce apoptosis in breast cancer cells. Poster

Abstract

Elesclomol Publications

Publication/Date Title Link
PLoS ONE: Research Article, published 11 Jan 2012 10.1371/journal.pone.0029798 Mitochondrial Electron Transport is the Cellular Target of the Oncology Drug Elesclomol.
Blackman et al.
Publication
Breast Cancer Research Treatment
June 2010;121(2):311-21.
Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells. 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. Publication
Molecular Cancer Therapeutics
August 2008; 7(8): 2319-2327.
Elesclomol induces cancer cell apoptosis through oxidative stress. Publication
Drug News Perspect
March 2007; 21(2): 123-124.
Molecule of the month: Elesclomol. Publication
Clin Cancer Res
January 2007; 13(2): 584-590.
Phase I clinical trial of STA-4783 in combination with Paclitaxel in patients with refractory solid tumors. Publication
Current Opinion in Investigational Drugs
2006; 7(6): 574-580.
Drug evaluation: STA-4783 - enhancing taxane efficacy by inducation of Hsp70. Publication

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References

Oxidative Stress and Cancer

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