Trial of Dichloroacetate (DCA) in Glioblastoma Multiforme (GBM)

Summary

Conduct a multicenter, open label Phase IIA trial of oral DCA in 40 surgical patients with recurrent GBM who have clinically indicated debulking surgery planned. No patients will be recruited at UF. Patients will be genotyped to establish safe dosing regimens and will be randomized to receive DCA (N=20) or no DCA (N=20) for one week prior to surgery. Deidentified blood and tumor tissue obtained at surgery will be assessed at UF for biochemical markers of DCA dynamics.

Timeline

Start

2022-07-01

Primary completion

2026-07-01

Completion

2026-08-31

Publications

• Background Dunbar EM, Coats BS, Shroads AL, Langaee T, Lew A, Forder JR, Shuster JJ, Wagner DA, Stacpoole PW. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest New Drugs. 2014 Jun;32(3):452-64. doi: 10.1007/s10637-013-0047-4. Epub 2013 Dec 3.
• Background Patel MS, Korotchkina LG, Sidhu S. Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex. J Mol Catal B Enzym. 2009 Nov 1;61(1-2):2-6. doi: 10.1016/j.molcatb.2009.05.001.
• Background Stacpoole PW. The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases. Aging Cell. 2012 Jun;11(3):371-7. doi: 10.1111/j.1474-9726.2012.00805.x. Epub 2012 Apr 4.
• Background Kankotia S, Stacpoole PW. Dichloroacetate and cancer: new home for an orphan drug? Biochim Biophys Acta. 2014 Dec;1846(2):617-29. doi: 10.1016/j.bbcan.2014.08.005. Epub 2014 Aug 23.
• Background DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016 May 27;2(5):e1600200. doi: 10.1126/sciadv.1600200. eCollection 2016 May.
• Background Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011 Aug 11;365(6):537-47. doi: 10.1056/NEJMra1011165. No abstract available.
• Background Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):349-53. doi: 10.1016/s0360-3016(01)01630-3.
• Background Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000 Feb 15;60(4):916-21.
• Background Walenta S, Schroeder T, Mueller-Klieser W. Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr Med Chem. 2004 Aug;11(16):2195-204. doi: 10.2174/0929867043364711.
• Background Park I, Larson PE, Zierhut ML, Hu S, Bok R, Ozawa T, Kurhanewicz J, Vigneron DB, Vandenberg SR, James CD, Nelson SJ. Hyperpolarized 13C magnetic resonance metabolic imaging: application to brain tumors. Neuro Oncol. 2010 Feb;12(2):133-44. doi: 10.1093/neuonc/nop043. Epub 2010 Jan 25.
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• Background Ippolito L, Morandi A, Giannoni E, Chiarugi P. Lactate: A Metabolic Driver in the Tumour Landscape. Trends Biochem Sci. 2019 Feb;44(2):153-166. doi: 10.1016/j.tibs.2018.10.011. Epub 2018 Nov 22.
• Background Feron O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother Oncol. 2009 Sep;92(3):329-33. doi: 10.1016/j.radonc.2009.06.025. Epub 2009 Jul 13.
• Background Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011 Apr 1;71(7):2550-60. doi: 10.1158/0008-5472.CAN-10-2828. Epub 2011 Feb 7.
• Background Goodwin ML, Jin H, Straessler K, Smith-Fry K, Zhu JF, Monument MJ, Grossmann A, Randall RL, Capecchi MR, Jones KB. Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment. Cancer Cell. 2014 Dec 8;26(6):851-862. doi: 10.1016/j.ccell.2014.10.003. Epub 2014 Nov 26.
• Background Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008 Dec;118(12):3930-42. doi: 10.1172/JCI36843. Epub 2008 Nov 20.
• Background Groussard C, Morel I, Chevanne M, Monnier M, Cillard J, Delamarche A. Free radical scavenging and antioxidant effects of lactate ion: an in vitro study. J Appl Physiol (1985). 2000 Jul;89(1):169-75. doi: 10.1152/jappl.2000.89.1.169.
• Background Sattler UG, Mueller-Klieser W. The anti-oxidant capacity of tumour glycolysis. Int J Radiat Biol. 2009 Nov;85(11):963-71. doi: 10.3109/09553000903258889.
• Background Calorini L, Peppicelli S, Bianchini F. Extracellular acidity as favouring factor of tumor progression and metastatic dissemination. Exp Oncol. 2012 Jul;34(2):79-84.
• Background Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A, Kreutz M. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006 Mar 1;107(5):2013-21. doi: 10.1182/blood-2005-05-1795. Epub 2005 Nov 8.
• Background Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA, Mueller-Klieser W. Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol. 2011 Aug;39(2):453-63. doi: 10.3892/ijo.2011.1055. Epub 2011 May 25.
• Background Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res. 2011 Nov 15;71(22):6921-5. doi: 10.1158/0008-5472.CAN-11-1457.
• Background Vyas S, Zaganjor E, Haigis MC. Mitochondria and Cancer. Cell. 2016 Jul 28;166(3):555-566. doi: 10.1016/j.cell.2016.07.002.
• Background Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, van der Burg SH, Verdegaal EM, Cascante M, Shlomi T, Gottlieb E, Peeper DS. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature. 2013 Jun 6;498(7452):109-12. doi: 10.1038/nature12154. Epub 2013 May 19.
• Background Pate KT, Stringari C, Sprowl-Tanio S, Wang K, TeSlaa T, Hoverter NP, McQuade MM, Garner C, Digman MA, Teitell MA, Edwards RA, Gratton E, Waterman ML. Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer. EMBO J. 2014 Jul 1;33(13):1454-73. doi: 10.15252/embj.201488598. Epub 2014 May 13.
• Background Kamarajugadda S, Stemboroski L, Cai Q, Simpson NE, Nayak S, Tan M, Lu J. Glucose oxidation modulates anoikis and tumor metastasis. Mol Cell Biol. 2012 May;32(10):1893-907. doi: 10.1128/MCB.06248-11. Epub 2012 Mar 19.
• Background Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 2013 Sep;123(9):3685-92. doi: 10.1172/JCI69741. Epub 2013 Sep 3.
• Background Stacpoole PW. Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer. J Natl Cancer Inst. 2017 Nov 1;109(11). doi: 10.1093/jnci/djx071.
• Background James MO, Jahn SC, Zhong G, Smeltz MG, Hu Z, Stacpoole PW. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther. 2017 Feb;170:166-180. doi: 10.1016/j.pharmthera.2016.10.018. Epub 2016 Oct 19.
• Background Han Z, Berendzen K, Zhong L, Surolia I, Chouthai N, Zhao W, Maina N, Srivastava A, Stacpoole PW. A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate. Mol Genet Metab. 2008 Apr;93(4):381-7. doi: 10.1016/j.ymgme.2007.10.131. Epub 2008 Feb 21.
• Background Li J, Kato M, Chuang DT. Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate. J Biol Chem. 2009 Dec 4;284(49):34458-67. doi: 10.1074/jbc.M109.065557. Epub 2009 Oct 15.
• Background Stacpoole PW. The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine--both or neither? Environ Health Perspect. 2011 Feb;119(2):155-8. doi: 10.1289/ehp.1002554. Epub 2010 Oct 4.
• Background Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006 Feb 14;66(3):324-30. doi: 10.1212/01.wnl.0000196641.05913.27.
• Background Shroads AL, Guo X, Dixit V, Liu HP, James MO, Stacpoole PW. Age-dependent kinetics and metabolism of dichloroacetate: possible relevance to toxicity. J Pharmacol Exp Ther. 2008 Mar;324(3):1163-71. doi: 10.1124/jpet.107.134593. Epub 2007 Dec 20.
• Background Shroads AL, Langaee T, Coats BS, Kurtz TL, Bullock JR, Weithorn D, Gong Y, Wagner DA, Ostrov DA, Johnson JA, Stacpoole PW. Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate. J Clin Pharmacol. 2012 Jun;52(6):837-49. doi: 10.1177/0091270011405664. Epub 2011 Jun 3.
• Background Abdelmalak M, Lew A, Ramezani R, Shroads AL, Coats BS, Langaee T, Shankar MN, Neiberger RE, Subramony SH, Stacpoole PW. Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab. 2013 Jun;109(2):139-43. doi: 10.1016/j.ymgme.2013.03.019. Epub 2013 Apr 6.
• Background Vallee A, Guillevin R, Vallee JN. Vasculogenesis and angiogenesis initiation under normoxic conditions through Wnt/beta-catenin pathway in gliomas. Rev Neurosci. 2018 Jan 26;29(1):71-91. doi: 10.1515/revneuro-2017-0032.
• Background Velpula KK, Guda MR, Sahu K, Tuszynski J, Asuthkar S, Bach SE, Lathia JD, Tsung AJ. Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma. Oncotarget. 2017 May 30;8(22):35639-35655. doi: 10.18632/oncotarget.16767.
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Drugs

Indications