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  Elesclomol

Elesclomol is a HSP-90 Inhibitor, and is a small-molecule bis(thio-hydrazide amide) with oxidative stress induction, pro-apoptotic, and potential antineoplastic activities. Elesclomol induces oxidative stress, creating high levels of reactive oxygen species (ROS), such as hydrogen peroxide, in both cancer cells and normal cells. Because tumor cells have elevated levels of ROS compared to normal cells, the increase in oxidative stress beyond baseline levels elevates ROS beyond sustainable levels, exhausting tumor cell antioxidant capacity, which may result in the induction of the mitochondrial apoptosis pathway. Normal cells are spared because the increase in the level of oxidative stress induced by this agent is below the threshold at which apoptosis is induced. Elesclomol is currently developed by Synta Pharmaceuticals Corp.  Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Synta Pharmaceuticals Corp.

Phase II study of Elesclomol. At 21 US sites, 53 patients were randomly assigned to E (elesclomol) + P (paciltaxel) , and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated. E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed. (source: J Clin Oncol. 2009 Nov 10;27(32):5452-8. )

Development status: Elesclomol (INN, codenamed STA-4783) is a drug that triggers apoptosis (programmed cell death) in cancer cells. It is being developed by Synta Pharmaceuticals and GlaxoSmithKline as a chemotherapy adjuvant, and has received both fast track and orphan drug status from the U.S. Food and Drug Administration for the treatment of metastatic melanoma.  Synta Pharmaceuticals announced on February 26, 2009 the suspension of all clinical trials involving Elesclomol due to safety concerns. In March 2010, Synta announced that the FDA had approved resuming clinical development of elesclomol, and that they expected to initiate one or more clinical trials for elesclomol in the second half of the year. In a small, randomized phase II study, elesclomol was shown to significantly increase progression-free survival in people with metastatic melanoma when given in addition to paclitaxel (Taxol). (soruce: http://en.wikipedia.org/wiki/Elesclomol).

Bioactivity: 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. 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.  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. Plans for future clinical trials with elesclomol will be announced later in 2010. (source: http://www.syntapharma.com/prdCancer.aspx).

Current developer:   Synta Pharmaceuticals Corp.

1: Blackman RK, Cheung-Ong K, Gebbia M, Proia DA, He S, Kepros J, Jonneaux A, Marchetti P, Kluza J, Rao PE, Wada Y, Giaever G, Nislow C. Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. PLoS One. 2012;7(1):e29798. Epub 2012 Jan 11. PubMed PMID: 22253786; PubMed Central PMCID: PMC3256171.

2: Wu L, Zhou L, Liu DQ, Vogt FG, Kord AS. LC-MS/MS and density functional theory study of copper(II) and nickel(II) chelating complexes of elesclomol (a novel anticancer agent). J Pharm Biomed Anal. 2011 Jan 25;54(2):331-6. Epub 2010 Sep 15. PubMed PMID: 20933353.

3: O'Day S, Gonzalez R, Lawson D, Weber R, Hutchins L, Anderson C, Haddad J, Kong S, Williams A, Jacobson E. Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. J Clin Oncol. 2009 Nov 10;27(32):5452-8. Epub 2009 Oct 13. PubMed PMID: 19826135.

4: Qu Y, Wang J, Sim MS, Liu B, Giuliano A, Barsoum J, Cui X. Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells. Breast Cancer Res Treat. 2010 Jun;121(2):311-21. Epub 2009 Jul 16. PubMed PMID: 19609669.

5: Wangpaichitr M, Wu C, You M, Maher JC, Dinh V, Feun LG, Savaraj N. N',N'-Dimethyl-N',N'-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS). Cancers (Basel). 2009;1(1):23-38. PubMed PMID: 20535236; PubMed Central PMCID: PMC2882109.

6: 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. Mol Cancer Ther. 2008 Aug;7(8):2319-27. PubMed PMID: 18723479.

7: Molecule of the month. Elesclomol and obatoclax mesylate. Drug News Perspect. 2008 Mar;21(2):123-4. PubMed PMID: 18389103.