Reversed metabolic reprogramming as a measure of cancer treatment efficacy in rat C6 glioma model

English version

Autoři: Keshav Datta ^aff001; Mette H. Lauritzen ^aff002; Milton Merchant ^aff003; Taichang Jang ^aff003; Shie-Chau Liu ^aff002; Ralph Hurd ^aff002; Lawrence Recht ^aff003; Daniel M. Spielman ^aff001
Působiště autorů: Department of Electrical Engineering, Stanford University, Stanford, California, United States of America ^aff001; Department of Radiology, Stanford University, Stanford, California, United States of America ^aff002; Department of Neurology, Stanford University, Stanford, California, United States of America ^aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0225313

Souhrn

Background

Metabolism in tumor shifts from oxidative phosphorylation to inefficient glycolysis resulting in overproduction of lactate (Warburg effect), and cancers may be effectively treated if this imbalance were corrected. The aim of this longitudinal study of glioblastoma in a rat model was to determine whether the ratio of lactate (surrogate marker for glycolysis) to bicarbonate (for oxidative phosphorylation), as measured via in vivo magnetic resonance imaging of hyperpolarized ¹³C-labeled pyruvate accurately predicts survival.

Methods

C6 Glioma implanted male Wistar rats (N = 26) were treated with an anti-vascular endothelial growth factor antibody B20.4.1.1 in a preliminary study to assess the efficacy of the drug. In a subsequent longitudinal survival study, magnetic resonance spectroscopic imaging (MRSI) was used to estimate [1-¹³C]Lactate and [1-¹³C]Bicarbonate in tumor and contralateral normal appearing brain of glioma implanted rats (N = 13) after injection of hyperpolarized [1-¹³C]Pyruvate at baseline and 48 hours post-treatment with B20.4.1.1.

Results

A survival of ~25% of B20.4.1.1 treated rats was noted in the preliminary study. In the longitudinal imaging experiment, changes in ¹³C Lactate, ¹³C Bicarbonate and tumor size measured at baseline and 48 hours post-treatment did not correlate with survival. ¹³C Lactate to ¹³C Bicarbonate ratio increased in all the 6 animals that succumbed to the tumor whereas the ratio decreased in 6 of the 7 animals that survived past the 70-day observation period.

Conclusions

¹³C Lactate to ¹³C Bicarbonate ratio (Lac/Bic) at 48 hours post-treatment is highly predictive of survival (p = 0.003). These results suggest a potential role for the ¹³C Lac/Bic ratio serving as a valuable measure of tumor metabolism and predicting therapeutic response.

Klíčová slova:

Drug metabolism – Glucose metabolism – Cancer treatment – Magnetic resonance imaging – Euthanasia – Metabolites – Glioma – Bicarbonates

Zdroje

1. Bensinger SJ and Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol. 2012; 23(4):352–361. doi: 10.1016/j.semcdb.2012.02.003 22406683

2. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324(5930):1029–1033 doi: 10.1126/science.1160809 19460998

3. Vander Heiden MG, Lunt SY, Dayton TL, Fiske BP, Israelsen WJ, Mattaini KR, et al. Metabolic pathway alterations that support cell proliferation. Cold Spring Harbor Symposium on Quant Biology. 2011; 76:325–334. doi: 10.1101/sqb.2012.76.010900 22262476

4. Gatenby RA and Gillies RJ. Why do cancers have high aerobic glycolysis. Nature Reviews Cancer. 2004; 4(11):891–899. doi: 10.1038/nrc1478 15516961

5. Corbin Z, Spielman DM, Recht L. A Metabolic Therapy for Malignant Glioma Requires a Clinical Measure. Curr Oncol Rep. 2017; 19(12):84. doi: 10.1007/s11912-017-0637-y 29098465

6. Warburg O. The metabolism of tumors. Arnold Constable London, UK (1930).

7. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927; 8(6): 519–530. doi: 10.1085/jgp.8.6.519 19872213

8. Ak P, Levine AJ. p53 and NF-kappaB: different strategies for responding to stress lead to a functional antagonism. FASEB J. 2010;24(10):3643–3652. Epub 2010/06/10. doi: 10.1096/fj.10-160549 20530750.

9. Golman K, Zandt RI, Lerche M, Pehrson R, Ardenkjaer-Larsen JH. Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Research, 2006; 66(22):10855–10860. doi: 10.1158/0008-5472.CAN-06-2564 17108122

10. Brindle KM, Bohndiek SE, Gallagher FA, Kettunen MI. Tumor imaging using hyperpolarized 13C magnetic resonance spectroscopy. Magn Reson Med, 2011; 66(2):505–519. doi: 10.1002/mrm.22999 21661043

11. Kurhanewicz J, Vigneron DB, Brindle K, Chekmenev EY, Comment A, Cunningham CH, et al. Analysis of cancer metabolism by imaging hyperpolarized nuclei: Prospects for translation of clinical research. Neoplasia. 2011; 13(2):81–97. doi: 10.1593/neo.101102 21403835

12. Chaumeil MM, Ozawa T, Park I, Scott K, James CD, Nelson SJ, et al. Hyperpolarized 13C MR spectroscopic imaging can be used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma. NeuroImage. 2012; 59(1):193–201. doi: 10.1016/j.neuroimage.2011.07.034 21807103

13. Chen AP, Chu W, Gu YP, Cunnhingham CH. Probing early tumor response to radiation therapy using hyperpolarized [1-13C]pyruvate in MDA-MD-231 xenografts. Plos One. 2013; 8(2):e56551. doi: 10.1371/journal.pone.0056551 23424666

14. Day SE, Kettunen MI, Cherukuri MK, Mitchell JB, Lizak MJ, Morris HD, et al. Detecting response of Rat C6 glioma tumors to radiotherapy using hyperpolarized [1-13C]Pyruvate and 13C magnetic resonance spectroscopic imaging. Magnetic Resonance in Medicine. 2011: 65(2):557–563. doi: 10.1002/mrm.22698 21264939

15. Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PE, Harzstark AL, Ferrone M, et al. Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate. Sci Transl Med. 2013; 5(198):198ra108. doi: 10.1126/scitranslmed.3006070 23946197

16. Radoul M, Chaumeil MM, Eriksson P, Wang AS, Phillips JJ, Ronen SM. MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival. Mol Cancer Ther. 2016; 15(5):1113–1122. doi: 10.1158/1535-7163.MCT-15-0769 26883274

17. Thomas P, Spielman DM, Recht L. The bevacizumab "pseudoresponse" in glioma: disappointment or opportunity? Brain Tumor, Current and Emerging Therapeutic Strategies, Abujamra A.L., Editor., InTech: Rijeka. 2011; p.53–66. doi: 10.5772/19845

18. Julia-Sape M, Candiota AP, Arús C. Cancer metabolism in a snapshot: MRS(I). NMR Biomed. 2019; 32:e4054. doi: 10.1002/nbm.4054 30633389

19. Park JM, Spielman DM, Josan S, Jang T, Merchant M, Hurd RE, et al. Hyperpolarized 13C-lactate to 13C-bicarbonate ratio as a biomarker for monitoring the acute response of anti-vascular endothelial growth factor (anti-VEGF) treatment. NMR Biomed. 2016; 29(5):650–659. doi: 10.1002/nbm.3509 26990457

20. Hurd RE, Yen YF, Tropp J, Pfefferbaum A, Spielman DM, Mayer D. Cerebral dynamics and metabolism of hyperpolarized [1-13C]pyruvate using time-resolved MR spectroscopic imaging. J Cereb Blood Flow Metab. 2010; 30(10):1734–1741. doi: 10.1038/jcbfm.2010.93 20588318

21. Warburg O. On the origin of cancer cells. Science. 1956; 123(3191):309–314. doi: 10.1126/science.123.3191.309 13298683

22. Zheng J. Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). Oncology Letters. 2012; 4(6):1151–1157. doi: 10.3892/ol.2012.928 23226794

23. Mayer D, Yen YF, Tropp J, Pfefferbaum A, Hurd RE, Spielman DM. Application of sub-second spiral chemical shift imaging to real-time multislice metabolic imaging of the rat in vivo after injection of hyperpolarized 13C1-pyruvate. Magn Reson Med. 2009; 62(3):557–564. doi: 10.1002/mrm.22041 19585607

24. Larson PEZ, Hu S, Lustig M, Kerr AB, Nelson SJ, Kurhanewicz J, et al. Fast Dynamic 3D MRSI with Compressed Sensing and Multiband Excitation Pulses for Hyperpolarized 13C Studies. Magn Reson Med. 2011; 65(3): 610–619. doi: 10.1002/mrm.22650 20939089

25. San-Galli F, Vrignaud P, Robert J, Coindre JM, Cohadon F. Assessment of the experimental model of transplanted C6 glioblastoma in Wistar rats. J Neurooncol. 1989; 7(3):299–304. doi: 10.1007/bf00172924 2795124

26. Iversen AB, Busk M, Bertelsen LB, Laustsen C, Munk OL, Nielsen T, et. al. The potential of hyperpolarized 13C magnetic resonance spectroscopy to monitor the effect of combretastatin based vascular disrupting agents. Acta Oncologica. 2017; 56(11):1626–1633. doi: 10.1080/0284186X.2017.1351622 28840759

27. Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer. 1996; 77(2):362–372. doi: 10.1002/(SICI)1097-0142(19960115)77:2<362::AID-CNCR20>3.0.CO;2-Z 8625246

28. Alves TR, Lima FR, Kahn SA, Lobo D, Dubois LG, Soletti R, et al. Glioblastoma cells: A heterogeneous and fatal tumor interacting with the parenchyma. Life Sciences. 2011; 89(15–16):532–539. doi: 10.1016/j.lfs.2011.04.022 21641917

29. Kurhanewicz J, Vigneron DB, Ardenkjaer-Larsen JH, Bankson JA, Brindle K, Cunningham CH, et. al. Hyperpolarized 13C MRI: Path to Clinical Translation in Oncology. Neoplasia. 2019; 21(1):1–16. doi: 10.1016/j.neo.2018.09.006 30472500

30. Grist JT, McLean MA, Riemer F, Schulte RF, Deen SS, Zaccagna F, et. al. Quantifying normal human brain metabolism using hyperpolarized [1-13C]pyruvate and magnetic resonance imaging. Neuroimage. 2019; 189:171–179. doi: 10.1016/j.neuroimage.2019.01.027 30639333

31. Hansen AE, Gutte H, Holst P, Johannesen HH, Rahbek S, Clemmensen AE, et. al. Combined hyperpolarized (13)C-pyruvate MRS and (18)F-FDG PET (hyperPET) estimates of glycolysis in canine cancer patients. Eur J Radiol. 2018; 103:6–12. doi: 10.1016/j.ejrad.2018.02.028 29803387

32. Provost C, Rozenblum-Beddok L, Nataf V, Merabtene F, Prignon A, Jean-No\l Talbot JN. [68Ga]RGD Versus [18F]FDG PET Imaging in Monitoring Treatment Response of a Mouse Model of Human Glioblastoma Tumor with Bevacizumab and/or Temozolomide. Mol Imaging Biol. 2019; 21(2):297–305. doi: 10.1007/s11307-018-1224-9 29948641