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Elesclomol

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Program Overview

About Elesclomol

Elesclomol is a novel, injectable, drug candidate that kills cancer cells by elevating oxidative stress levels beyond a breaking point, triggering programmed cell death. In preclinical models elesclomol showed killing of a broad range of cancer cell types at high doses, and an ability to enhance the efficacy of certain chemotherapy agents, with minimal additional toxicity, at moderate doses. In a recent 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). Elesclomol is currently enrolling patients in the SYMMETRY trial - a 630-patient, pivotal, confirmatory Phase 3 clinical trial in metastatic melanoma, which has the same design as the Phase 2b trial. Results are expected in early 2009. Phase 2 trials in other indications, and in combination with other agents, are planned.

Elesclomol Mechanism of Action

Elesclomol acts through a novel mechanism of action with broad and exciting 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 reactive oxygen species (ROS) – inside cancer cells.  This increase in ROS is observed through measuring 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 prolonged elevation of ROS inside cancer cells induced by elesclomol causes the cell to exceed a critical breaking point and undergo programmed cell death, or apoptosis. The triggering of the mitochondrial apoptosis pathway is observed within the first six hours of applying elesclomol, as shown below:

Cancer cells operate at a much higher intrinsic level of ROS than normal cells, and have a greatly reduced anti-oxidant capacity compared to normal cells. This leaves them more vulnerable to an agent such as elesclomol that elevates oxidative stress. In similar experiments at similar doses, elesclomol has been found to have little to no impact on normal cells.

This mechanism therefore represents a novel anti-cancer strategy – a novel way of differentiating, and selectively killing, cancer cells vs. normal cells. It is this differentiation that we believe has led to the high therapeutic index - strong anti-tumor activity with favorable safety profile - seen in our preclinical models.

The potent anti-tumor activity and high therapeutic index are promising indicators of the exciting potential for this mechanism category in treating a broad range of cancer types.

More on ROS and cancer.
References on oxidative stress and cancer.

About Melanoma

Melanoma, the most deadly form of skin cancer, arises from melanocytes, the pigment producing cells of the skin. According to the American Cancer Society, the incidence of melanoma in the United States was 62,000 in 2006, and was the cause of 8,000 deaths. While melanoma accounts for approximately five percent of all skin cancers, it causes about 75% of all skin cancer-related deaths. If diagnosed and surgically removed while localized in the outermost skin layer, melanoma is potentially curable; however, for patients with deeper lesions or metastatic disease, the prognosis is poor, with limited available treatments and an expected survival of only six to nine months. The incidence of melanoma has increased more rapidly than any other cancer during the past ten years.

According to a Datamonitor report, despite R&D efforts to improve disease prognosis, little progress has been made over the past three decades. Due to melanoma’s cutaneous location and its high metastatic potential, the management of melanoma remains a major clinical challenge. Stage IV patients are burdened with a very poor prognosis, with five-year survival rates of between 6.7% and 18.8%, depending on the site of metastasis.

A recent Datamonitor report also stated that current treatment for advanced stage melanoma yields response rates of approximately 20% or less, indicating that the disease is poorly served by currently available therapy. In addition, most of the drugs administered to patients are associated with a high degree of toxicity, in many cases reducing patient quality of life. The study quotes a key opinion leader, who states that "Both for stage III and IV patients, the lack of effective therapy that is able to control the progression of metastatic disease [and] that offers some sort of symptom benefit for patients is arguably the greatest unmet need. We do not have a therapy that alters the natural history of melanoma and improves overall survival for patients".

  • Visit The Billy Foundation to view statistics on melanoma.
  • For more information, visit the melanoma section of the Cancer Institute’s website.

Presentations

References

Oxidative Stress and Cancer
  • B Ramanathan et al: Resistance to Paclitaxel is Proportional to Cellular Total Antioxidant Capacity, Cancer Research 65: (18), September 2005, 8455-8460.
  • Fruehauf, JP, Meyskens, FL: Reactive Oxygen Species: A Breath of Life or Death? Clinical Cancer Research; 13(3) February 2007, 789-794.
  • 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.
  • Pelicano, H et al: ROS stress in cancer cells and therapeutic implications, Drug Resistance Updates 7 (2004) 97-110.
  • 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, PT: Reactive oxygen species in cancer cells: Live by the sword, die by the sword, Cancer Cell, September 2006, 175-176.
Melanoma – Review Articles
  • Balch, CM et al, Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma, Journal of Clinical Oncology, Vol. 19, No. 16, 2001, 3635-3648.
  • Korn E, et al: Meta-Analysis of Phase II Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future Phase II Trials. J Clin Oncol 2008; 26(4):527-534.
  • NCCN, Melanoma Guidelines V. III, September 2005.
  • Tarhini, A., Agarwala, S.: Cutaneous melanoma; available therapy for metastatic disease. Dermatologic therapy, 2006; 19: 19-25.
  • Thompson, JF et al,: Cutaneous Melanoma, The Lancet, 2005, Vol 365, 687-701.
Melanoma – Historical Clinical Trials
  • Click here for references on historical clinical trials.

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