Skip to main content

Advertisement

Log in

Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors

Investigational New Drugs Aims and scope Submit manuscript

Summary

Background Recurrent malignant brain tumors (RMBTs) carry a poor prognosis. Dichloroacetate (DCA) activates mitochondrial oxidative metabolism and has shown activity against several human cancers. Design We conducted an open-label study of oral DCA in 15 adults with recurrent WHO grade III – IV gliomas or metastases from a primary cancer outside the central nervous system. The primary objective was detection of a dose limiting toxicity for RMBTs at 4 weeks of treatment, defined as any grade 4 or 5 toxicity, or grade 3 toxicity directly attributable to DCA, based on the National Cancer Institute’s Common Toxicity Criteria for Adverse Events, version 4.0. Secondary objectives involved safety, tolerability and hypothesis-generating data on disease status. Dosing was based on haplotype variation in glutathione transferase zeta 1/maleylacetoacetate isomerase (GSTZ1/MAAI), which participates in DCA and tyrosine catabolism. Results Eight patients completed at least 1 four week cycle. During this time, no dose-limiting toxicities occurred. No patient withdrew because of lack of tolerance to DCA, although 2 subjects experienced grade 0–1 distal parasthesias that led to elective withdrawal and/or dose-adjustment. All subjects completing at least 1 four week cycle remained clinically stable during this time and remained on DCA for an average of 75.5 days (range 26–312). Conclusions Chronic, oral DCA is feasible and well-tolerated in patients with recurrent malignant gliomas and other tumors metastatic to the brain using the dose range established for metabolic diseases. The importance of genetic-based dosing is confirmed and should be incorporated into future trials of chronic DCA administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig 4
Fig. 5

References

  1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA (2000) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83(5):588–593

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Villà S, Weber DC, Moretones C, Mañes A, Combescure C, Jové J, Puyalto P, Cuadras P, Bruna J, Verger E, Balañà C, Graus F (2011) Validation of the new Graded Prognostic Assessment scale for brain metastases: a multicenter prospective study. Radiat Oncol 6:23. doi:10.1186/1748-717X-6-23

    Article  PubMed Central  PubMed  Google Scholar 

  3. Furman W. Everolimus for Treating Pediatric Patients with Recurrent or Refractory Tumors (2005) Available from http://clinicaltrials.gov/ct2/show/NCT00187174?term=recurrent+tumors+AND+brain&rank=12

  4. Caffo M, Barresi V, Caruso G, Cutugno M, La Fata G, Venza M, Alafaci C, Tomasello F (2013) Innovative therapeutic strategies in the treatment of brain metastases. Int J Mol Sci 14(1):2135–2174

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Yeung SJ, Pan J, Lee MH (2008) Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell Mol Life Sci 65(24):3981–3999

    Article  CAS  PubMed  Google Scholar 

  7. Contractor T, Harris CR (2012) p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res 72(2):560–567

    Article  CAS  PubMed  Google Scholar 

  8. Sutendra G, Michelakis ED (2013) Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol 3:38

    Article  PubMed Central  PubMed  Google Scholar 

  9. Stacpoole PW (1989) The pharmacology of dichloroacetate. Metabolism 38(11):1124–1144

    Article  CAS  PubMed  Google Scholar 

  10. Park JM, Recht LD, Josan S, Merchant M, Jang T, Yen YF, Hurd RE, Spielman DM, Mayer D (2013) Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized (13)C magnetic resonance spectroscopic imaging. Neuro Oncol 15(4):433–441

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Stacpoole PW (2011) The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine–both or neither? Environ Health Perspect 119(2):155–158

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Shroads AL, Langaee T, Coats BS, Kurtz TL, Bullock JR, Weithorn D, Gong Y, Wagner DA, Ostrov DA, Johnson JA, Stacpoole PW (2012) Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate. J Clin Pharmacol 52(6):837–849

    Article  CAS  PubMed  Google Scholar 

  13. Berendzen K, Theriaque DW, Shuster J, Stacpoole PW (2006) Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion 6(3):126–135

    Article  CAS  PubMed  Google Scholar 

  14. Simpson NE, Han Z, Berendzen KM, Sweeney CA, Oca-Cossio JA, Constantinidis I, Stacpoole PW (2006) Magnetic resonance spectroscopic investigation of mitochondrial fuel metabolism and energetics in cultured human fibroblasts: effects of pyruvate dehydrogenase complex deficiency and dichloroacetate. Mol Genet Metab 89(1–2):97–105

    Article  CAS  PubMed  Google Scholar 

  15. Glushakova LG, Judge S, Cruz A, Pourang D, Mathews CE, Stacpoole PW (2011) Increased superoxide accumulation in pyruvate dehydrogenase complex deficient fibroblasts. Mol Genet Metab 104(3):255–260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K + channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1):37–51

    Article  CAS  PubMed  Google Scholar 

  17. Sutendra G, Dromparis P, Kinnaird A, Stenson TH, Haromy A, Parker JM, McMurtry MS, Michelakis ED (2013) Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. Oncogene 32(13):1638–1650

    Article  CAS  PubMed  Google Scholar 

  18. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2(31):31–34

    Article  Google Scholar 

  19. Zhou ZH, McCarthy DB, O'Connor CM, Reed LJ, Stoops JK (2001) The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proc Natl Acad Sci USA 98(26):14802–14807

    Google Scholar 

  20. Smolle M, Prior AE, Brown AE, Cooper A, Byron O, Lindsay JG (2006) A new level of architectural complexity in the human pyruvate dehydrogenase complex. J Biol Chem 281(28):19772–19780

    Google Scholar 

  21. Shroads AL, Guo X, Dixit V, Liu HP, James MO, Stacpoole PW (2008) Age-dependent kinetics and metabolism of dichloroacetate: possible relevance to toxicity. J Pharmacol Exp Ther 324(3):1163–1171

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Mitchell G, Lambert M, Tanguay R. Hypertyrosinemia (1995) In Schriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, Inc., Health Professions Division, New York, pp. 1077–106

  23. Karnofsky D (ed) (1949) The clinical evaluation of chemotherapeutic agents in cancer. Columbia University Press, New York

    Google Scholar 

  24. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655

    Article  CAS  PubMed  Google Scholar 

  25. Nabors LB, Supko JG, Rosenfeld M, Chamberlain M, Phuphanich S, Batchelor T, Desideri S, Ye X, Wright J, Gujar S, Grossman SA, New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium (2011) Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma. Neuro Oncol 13(12):1324–1330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Grossman SA, Ye X, Peereboom D, Rosenfeld MR, Mikkelsen T, Supko JG, Desideri S, Adult Brain Tumor Consortium (2012) Phase I study of terameprocol in patients with recurrent high-grade glioma. Neuro Oncol 14(4):511–517

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM, Felitsyn NM, Gilmore RL, Greer M, Henderson GN, Hutson AD, Neiberger RE, O'Brien RG, Perkins LA, Quisling RG, Shroads AL, Shuster JJ, Silverstein JH, Theriaque DW, Valenstein E (2006) Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117(5):1519–1531

    Article  PubMed  Google Scholar 

  28. Kreisl TN, Kim L, Moore K, Duic P, Kotliarova S, Walling J, Musib L, Thornton D, Albert PS, Fine HA (2009) A phase I trial of enzastaurin in patients with recurrent gliomas. Clin Cancer Res 15(10):3617–3623

    Article  CAS  PubMed  Google Scholar 

  29. Kubicek GJ, Werner-Wasik M, Machtay M, Mallon G, Myers T, Ramirez M, Andrews D, Curran WJ Jr, Dicker AP (2009) Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies. Int J Radiat Oncol Biol Phys 74(2):433–439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Yan Z, Henderson GN, James MO, Stacpoole PW (1997) Determination of dichloroacetate and its metabolites in human plasma by gas chromatography–mass spectrometry. J Chromatogr B Biomed Sci Appl 703(1–2):75–84

    Article  CAS  PubMed  Google Scholar 

  31. Henderson GN, Whalen PO, Darr RA, Curry SH, Derendorf H, Baumgartner TG, Stacpoole PW (1994) Development of an oral drug formulation for dichloroacetate and thiamine. Drug Dev Indust Pharm 20(15):2425–2437

    Article  CAS  Google Scholar 

  32. Langaee T, Ronaghi M (2005) Genetic variation analyses by pyrosequencing. Mutat Res 673:96–102

    Article  Google Scholar 

  33. Stephens M, Smith NK, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Stacpoole PW, Wagner DW (2012) Rapid breath test for in vivo determination of human pyruvate dehydrogenase complex activity. UMDF Annual Meeting, Bethesda, MD, June 12–16

  35. Wagner DA, Schatz R, Coston R, Curington C, Bolt D, Toskes PP (2011) A new 13C breath test to detect vitamin B12 deficiency: a prevalent and poorly diagnosed health problem. J Breath Res 5(4):046001

    Article  PubMed Central  PubMed  Google Scholar 

  36. Stacpoole PW, Nagaraja NV, Hutson AD (2003) Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol 43(7):683–691

    Article  CAS  PubMed  Google Scholar 

  37. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organization for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  PubMed  Google Scholar 

  38. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8(7):1277–1280

    CAS  PubMed  Google Scholar 

  39. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972

    Article  PubMed  Google Scholar 

  40. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 329(Pt 1):191–196

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. 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 (2006) Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66(3):324–330

    Article  CAS  PubMed  Google Scholar 

  42. Abdelmalak M, Lew A, Ramezani R, Shroads AL, Coats BS, Langaee T, Shankar MN, Neiberger RE, Subramony SH, Stacpoole PW (2013) Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab 109:139–143

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Stacpoole PW, Gilbert LR, Neiberger RE, Carney PR, Valenstein E, Theriaque DW, Shuster JJ (2008) Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics 121(5):e1223–e1228

    Article  PubMed Central  PubMed  Google Scholar 

  44. Stockwin LH, Yu SX, Borgel S, Hancock C, Wolfe TL, Phillips LR, Hollingshead MG, Newton DL (2010) Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int J Cancer 127(11):2510–2519

    Article  CAS  PubMed  Google Scholar 

  45. Bersin RM, Stacpoole PW (1997) Dichloroacetate as metabolic therapy for myocardial ischemia and failure. Am Heart J 134(5 Pt 1):841–855

    Article  CAS  PubMed  Google Scholar 

  46. Piao L, Marsboom G, Archer SL (2010) Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure. J Mol Med (Berl) 88(10):1011–1020

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Stacpoole PW (2012) The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases. Aging Cell 11(3):371–377

    Article  CAS  PubMed  Google Scholar 

  48. Shen YC, Ou DL, Hsu C, Lin KL, Chang CY, Lin CY, Liu SH, Cheng AL (2013) Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br J Cancer 108(1):72–81

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Fujiwara S, Kawano Y, Yuki H, Okuno Y, Nosaka K, Mitsuya H, Hata H (2013) PDK1 inhibition is a novel therapeutic target in multiple myeloma. Br J Cancer 108(1):170–178

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Ohashi T, Akazawa T, Aoki M, Kuze B, Mizuta K, Ito Y, Inoue N (2013) Dichloroacetate improves immune dysfunction cuased by tumor-secreted lactic acid and increases anti-tumor immunoreactivity. Intr J Cancer. doi:10.1002/ijc.28114

    Google Scholar 

  51. Sanchez WY, McGee SL, Connor T, Mottram B, Wilkinson A, Whitehead JP, Vuckovic S, Catley L (2013) Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib. Br J Cancer 108(8):1624–1633

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Wu CA, Chao Y, Shiah SG, Lin WW (2013) Nutrient deprivation induces the Warburg effect through ROS/AMPK-dependent activation of pyruvate dehydrogenase kinase. Biochim Biophys Acta 1833(5):1147–1156

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to the DSMB members for their dedication to this trial and to Ms. Candace Caputo for editorial assistance.

Funding

This study was funded by Reliable Cancer Therapies, Brussels, Belgium, the Ocala Royal Dames Foundation, Ocala, FL, the Preston A. Wells, Jr., Center for Brain Tumor Therapy and a National Institutes of Health Clinical and Translational Science Award UL1 TR000064.

Conflict of interest disclosures

PWS holds investigator INDs for DCA. DAW is President, Metabolic Solutions, Inc.

Authors’ contributions

EMD, JJS and PWS developed the study design; EMD and BSC screened and enrolled subjects; EMD, PWS and BSC evaluated and treated patients; TL performed and interpreted the genotyping; ALS conducted mass spectrometric analyses; EMD, BSC and PWS analyzed routine clinical and imaging data; JRF and EMD analyzed exploratory imaging data; JJS reviewed interim safety data, PWS and DAW designed the breath test procedures; BSC conducted the pyruvate breath test; DAW analyzed 13CO2 breath samples; EMD, PWS and DAW wrote the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P. W. Stacpoole.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dunbar, E.M., Coats, B.S., Shroads, A.L. et al. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest New Drugs 32, 452–464 (2014). https://doi.org/10.1007/s10637-013-0047-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-013-0047-4

Keywords

Navigation