Principal Investigator

Robert
Dantzer
Awardee Organization

University Of Tx Md Anderson Can Ctr
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

The Metabolic Basis of Cancer-Related Fatigue

– Cancer-related fatigue is one of the most common and disruptive symptoms experienced by patients. It is often present at the time of diagnosis, worsens throughout treatment, and persists well after the cessation of treatment in a significant proportion of patients. The specific mechanisms responsible for fatigue remain largely unknown. Consequently, there are no mechanism-guided therapies for fatigue and the primary approach to patients reporting severe fatigue is education and counseling in the self-management of fatigue. Although conservation of energy is an important strategy in the management of fatigue, the possibility that cancer-related fatigue originates from alterations in energy metabolism has not been examined. The present project fills this void. Our working hypothesis is that cancer-related fatigue is the behavioral consequence of the excess metabolic demand imposed on the organism by the tumor and the inflammation it is possibly associated with. The relative metabolic inefficiency that results from this condition is worsened by the mitochondrial impairment that develops in peripheral tissues and the brain in response to chemotherapy and radiotherapy. To test our hypothesis, we will use two syngeneic murine models of cancer that both respond to a combination of cisplatin and local irradiation, a non-inflammatory model mimicking human papilloma virus-related head and neck cancer, and an inflammatory model represented by Lewis lung carcinoma. We will measure behavioral fatigue in both conditions by decreased voluntary wheel running and alterations in motivated behavior to account for the motivational component of fatigue. In Aim 1, we will determine whether inflammation associated with the tumor and its treatment needs to propagate to the brain for fatigue to develop. This will be done by comparing the time course of inflammation at the periphery and in the brain to that of fatigue before intervening to either block immune signaling molecules by passive immunization or deplete the innate immune cells that mediate the inflammatory process at the periphery and in the brain. In Aim 2, we will test the hypothesis that metabolic reprogramming by cancer and inflammation leads to a condition of relative energy metabolism deficiency that is exacerbated by cancer therapy-induced mitochondrial dysfunction. This will be done by determining the association between metabolic reprogramming and behavioral fatigue before assessing whether intensifying mitochondrial damage exacerbates the behavioral and metabolic phenotypes of fatigue while preventing mitochondrial damage has the reverse effect. In Aim 3, we will test the hypothesis that activation of cytosol DNA sensors by self DNA leaking from mitochondria and cell nuclei triggers this whole process. This research should help understand and treat cancer-related fatigue.

Publications

  • Dantzer R. Mental health, war trauma, and migration: The contribution of Comprehensive Psychoneuroendocrinology. Comprehensive psychoneuroendocrinology. 2023 Jan 19;13:100168. doi: 10.1016/j.cpnec.2023.100168. eCollection 2023 Feb. PMID: 36873730
  • Maj MA, Ma J, Krukowski KN, Kavelaars A, Heijnen CJ. Inhibition of Mitochondrial p53 Accumulation by PFT-μ Prevents Cisplatin-Induced Peripheral Neuropathy. Frontiers in molecular neuroscience. 2017 Apr 18;10:108. doi: 10.3389/fnmol.2017.00108. eCollection 2017. PMID: 28458631
  • Raizen DM, Mullington J, Anaclet C, Clarke G, Critchley H, Dantzer R, Davis R, Drew KL, Fessel J, Fuller PM, Gibson EM, Harrington M, Ian Lipkin W, Klerman EB, Klimas N, Komaroff AL, Koroshetz W, Krupp L, Kuppuswamy A, Lasselin J, Lewis LD, Magistretti PJ, Matos HY, Miaskowski C, Miller AH, Nath A, Nedergaard M, Opp MR, Ritchie MD, Rogulja D, Rolls A, Salamone JD, Saper C, Whittemore V, Wylie G, Younger J, Zee PC, Craig Heller H. Beyond the symptom: the biology of fatigue. Sleep. 2023 Sep 8;46. (9). PMID: 37224457
  • Grossberg AJ, Vichaya EG, Gross PS, Ford BG, Scott KA, Estrada D, Vermeer DW, Vermeer P, Dantzer R. Interleukin 6-independent metabolic reprogramming as a driver of cancer-related fatigue. Brain, behavior, and immunity. 2020 Aug;88:230-241. Epub 2020 May 16. PMID: 32428555
  • Arnone D, Saraykar S, Salem H, Teixeira AL, Dantzer R, Selvaraj S. Role of Kynurenine pathway and its metabolites in mood disorders: A systematic review and meta-analysis of clinical studies. Neuroscience and biobehavioral reviews. 2018 Sep;92:477-485. Epub 2018 Jun 22. PMID: 29940237
  • Vichaya EG, Vermeer DW, Budac D, Lee A, Grossberg A, Vermeer PD, Lee JH, Dantzer R. Inhibition of Indoleamine 2,3 Dioxygenase Does Not Improve Cancer-Related Symptoms in a Murine Model of Human Papilloma Virus-Related Head and Neck Cancer. International journal of tryptophan research : IJTR. 2019 Aug 28;12:1178646919872508. doi: 10.1177/1178646919872508. eCollection 2019. PMID: 31496720
  • Lei Y, VanPortfliet JJ, Chen YF, Bryant JD, Li Y, Fails D, Torres-Odio S, Ragan KB, Deng J, Mohan A, Wang B, Brahms ON, Yates SD, Spencer M, Tong CW, Bosenberg MW, West LC, Shadel GS, Shutt TE, Upton JW, Li P, West AP. Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity. Cell. 2023 Jul 6;186(14):3013-3032.e22. Epub 2023 Jun 22. PMID: 37352855
  • Dantzer R. Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches. Current topics in behavioral neurosciences. 2017;31:117-138. PMID: 27225497
  • Vichaya EG, Laumet G, Christian DL, Grossberg AJ, Estrada DJ, Heijnen CJ, Kavelaars A, Dantzer R. Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2019 Jan;44(2):364-371. Epub 2018 Apr 27. PMID: 29760410
  • Paul ER, Schwieler L, Erhardt S, Boda S, Trepci A, Kämpe R, Asratian A, Holm L, Yngve A, Dantzer R, Heilig M, Hamilton JP, Samuelsson M. Peripheral and central kynurenine pathway abnormalities in major depression. Brain, behavior, and immunity. 2022 Mar;101:136-145. Epub 2022 Jan 6. PMID: 34999196
  • Chelette B, Chidomere CL, Dantzer R. The GDF15-GFRAL axis mediates chemotherapy-induced fatigue in mice. Brain, behavior, and immunity. 2023 Feb;108:45-54. Epub 2022 Nov 24. PMID: 36427806
  • Dantzer R. Evolutionary Aspects of Infections: Inflammation and Sickness Behaviors. Current topics in behavioral neurosciences. 2023;61:1-14. PMID: 35505054
  • Vichaya EG, Darpolor JK, Gross PS, Molkentine JM, Vermeer DW, Vermeer PD, Lee JH, Taniguchi CM, Dantzer R. Associative learning contributes to the persistence of fatigue-like behavior in male mice in a model of cancer survivorship. Brain, behavior, and immunity. 2023 Jan;107:296-304. Epub 2022 Oct 30. PMID: 36323360
  • Vichaya EG, Ford BG, Quave CB, Rishi MR, Grossberg AJ, Dantzer R. Toll-like receptor 4 mediates the development of fatigue in the murine Lewis Lung Carcinoma model independently of activation of macrophages and microglia. Psychoneuroendocrinology. 2020 Dec;122:104874. Epub 2020 Sep 16. PMID: 32979744
  • Molkentine JM, Fujimoto TN, Horvath TD, Grossberg AJ, Garcia CJG, Deorukhkar A, de la Cruz Bonilla M, Lin D, Samuel ELG, Chan WK, Lorenzi PL, Piwnica-Worms H, Dantzer R, Tour JM, Mason KA, Taniguchi CM. Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation. Scientific reports. 2019 Feb 13;9(1):1949. PMID: 30760738
  • Fleshner M, Epperson N, Dantzer R. Those we have lost: Dr. Mark L. Laudenslager. Psychoneuroendocrinology. 2021 Feb;124:105126. Epub 2020 Dec 31. PMID: 34131360
  • Madeo M, Colbert PL, Vermeer DW, Lucido CT, Cain JT, Vichaya EG, Grossberg AJ, Muirhead D, Rickel AP, Hong Z, Zhao J, Weimer JM, Spanos WC, Lee JH, Dantzer R, Vermeer PD. Cancer exosomes induce tumor innervation. Nature communications. 2018 Oct 16;9(1):4284. PMID: 30327461
  • Casaril AM, Vichaya EG, Rishi MR, Ford BG, Dantzer R. Lipopolysaccharide does not alter behavioral response to successive negative contrast in mice. Psychopharmacology. 2021 Mar;238(3):691-697. Epub 2021 Jan 7. PMID: 33410982
  • Chaskiel L, Dantzer R, Konsman JP. Brain Perivascular Macrophages Do Not Mediate Interleukin-1-Induced Sickness Behavior in Rats. Pharmaceuticals (Basel, Switzerland). 2021 Oct 11;14. (10). PMID: 34681254
  • Dantzer R. Love and fear in the times of sickness. Comprehensive psychoneuroendocrinology. 2021 May;6. Epub 2021 Feb 22. PMID: 34327337
  • Dantzer R. Can Immunopsychiatry Help in Understanding the Basis of Sex Differences in Major Depressive Disorder? Biological psychiatry. Cognitive neuroscience and neuroimaging. 2019 Jul;4(7):606-607. PMID: 31279402
  • Vichaya EG, Dantzer R. Inflammation-induced motivational changes: Perspective gained by evaluating positive and negative valence systems. Current opinion in behavioral sciences. 2018 Aug;22:90-95. Epub 2018 Feb 10. PMID: 29888301
  • LaVoy EC, Fagundes CP, Dantzer R. Exercise, inflammation, and fatigue in cancer survivors. Exercise immunology review. 2016;22:82-93. PMID: 26853557
  • Dantzer R, Cohen S, Russo SJ, Dinan TG. Resilience and immunity. Brain, behavior, and immunity. 2018 Nov;74:28-42. Epub 2018 Aug 10. PMID: 30102966
  • Bryant JD, Kodali M, Shuai B, Menissy SS, Graves PJ, Phan TT, Dantzer R, Shetty AK, Ciaccia West L, West AP. Neuroimmune mechanisms of cognitive impairment in a mouse model of Gulf War illness. Brain, behavior, and immunity. 2021 Oct;97:204-218. Epub 2021 Jul 29. PMID: 34333111
  • Dantzer R. Editorial. Psychoneuroendocrinology. 2022 Nov;145:105941. Epub 2022 Sep 21. PMID: 36184378
  • Colpo GD, Leboyer M, Dantzer R, Trivedi MH, Teixeira AL. Immune-based strategies for mood disorders: facts and challenges. Expert review of neurotherapeutics. 2018 Feb;18(2):139-152. Epub 2017 Nov 27. PMID: 29179585
  • Lacourt TE, Vichaya EG, Chiu GS, Dantzer R, Heijnen CJ. The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Frontiers in behavioral neuroscience. 2018 Apr 26;12:78. doi: 10.3389/fnbeh.2018.00078. eCollection 2018. PMID: 29755330
  • Vichaya EG, Ford BG, Moltenkine JM, Taniguchi CM, Phillip West A, Dantzer R. Sex differences in the behavioral and immune responses of mice to tumor growth and cancer therapy. Brain, behavior, and immunity. 2021 Nov;98:161-172. Epub 2021 Aug 19. PMID: 34418499
  • Casaril AM, Dantzer R, Bas-Orth C. Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in Inflammation-Associated Depression. Frontiers in neuroscience. 2021 Nov 1;15:725547. doi: 10.3389/fnins.2021.725547. eCollection 2021. PMID: 34790089
  • Scott K, Phan TT, Boukelmoune N, Heijnen CJ, Dantzer R. Chronic restraint stress impairs voluntary wheel running but has no effect on food-motivated behavior in mice. Brain, behavior, and immunity. 2023 Jan;107:319-329. Epub 2022 Oct 29. PMID: 36349643
  • Coppock JD, Vermeer PD, Vermeer DW, Lee KM, Miskimins WK, Spanos WC, Lee JH. mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC. Oncotarget. 2016 Apr 26;7(17):24228-41. PMID: 27015118
  • Vichaya EG, Malik S, Sominsky L, Ford BG, Spencer SJ, Dantzer R. Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats. Journal of neuroinflammation. 2020 May 31;17(1):172. PMID: 32475344
  • Vermeer DW, Coppock JD, Zeng E, Lee KM, Spanos WC, Onken MD, Uppaluri R, Lee JH, Vermeer PD. Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis. Oncotarget. 2016 Apr 26;7(17):24194-207. PMID: 27013584
  • Phan TT, Scott KS, Chelette B, Phillip West A, Dantzer R. The fatigue-inducing effects of cancer and its therapy are characterized by decreased physical activity in the absence of any motivational deficit. Brain, behavior, and immunity. 2024 Mar;117:205-214. Epub 2024 Jan 18. PMID: 38244945
  • Meier TB, Drevets WC, Teague TK, Wurfel BE, Mueller SC, Bodurka J, Dantzer R, Savitz J. Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression. Brain, behavior, and immunity. 2018 Jan;67:59-64. Epub 2017 Sep 1. PMID: 28867283
  • Scott KS, Chelette B, Chidomere C, Phillip West A, Dantzer R. Cisplatin decreases voluntary wheel-running activity but does not impair food-motivated behavior in mice. Brain, behavior, and immunity. 2023 Jul;111:169-176. Epub 2023 Apr 17. PMID: 37076053
  • Dantzer R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiological reviews. 2018 Jan 1;98(1):477-504. PMID: 29351513
  • Vichaya EG, Gross PS, Estrada DJ, Cole SW, Grossberg AJ, Evans SE, Tuvim MJ, Dickey BF, Dantzer R. Lipocalin-2 is dispensable in inflammation-induced sickness and depression-like behavior. Psychopharmacology. 2019 Oct;236(10):2975-2982. Epub 2019 Feb 26. PMID: 30806746
  • Grossberg AJ, Vichaya EG, Christian DL, Molkentine JM, Vermeer DW, Gross PS, Vermeer PD, Lee JH, Dantzer R. Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling. Cancer research. 2018 Feb 1;78(3):695-705. Epub 2017 Dec 7. PMID: 29217760
  • Dantzer R. From Stress Sensitization to Microglial Priming and Vice Versa: A New Era of Research in Biological Psychiatry. Biological psychiatry. 2019 Apr 15;85(8):619-620. PMID: 30922465
  • Chiu GS, Maj MA, Rizvi S, Dantzer R, Vichaya EG, Laumet G, Kavelaars A, Heijnen CJ. Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function. Cancer research. 2017 Feb 1;77(3):742-752. Epub 2016 Nov 22. PMID: 27879267
  • Vichaya EG, Vermeer DW, Christian DL, Molkentine JM, Mason KA, Lee JH, Dantzer R. Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer. Psychoneuroendocrinology. 2017 May;79:59-66. Epub 2017 Feb 11. PMID: 28259044
  • Vichaya EG, Chiu GS, Krukowski K, Lacourt TE, Kavelaars A, Dantzer R, Heijnen CJ, Walker AK. Mechanisms of chemotherapy-induced behavioral toxicities. Frontiers in neuroscience. 2015 Apr 21;9:131. doi: 10.3389/fnins.2015.00131. eCollection 2015. PMID: 25954147
  • Zhou W, Kavelaars A, Heijnen CJ. Metformin Prevents Cisplatin-Induced Cognitive Impairment and Brain Damage in Mice. PloS one. 2016 Mar 28;11(3):e0151890. doi: 10.1371/journal.pone.0151890. eCollection 2016. PMID: 27018597
  • Khandaker GM, Stochl J, Zammit S, Lewis G, Dantzer R, Jones PB. Association between circulating levels of C-reactive protein and positive and negative symptoms of psychosis in adolescents in a general population birth cohort. Journal of psychiatric research. 2021 Nov;143:534-542. Epub 2020 Nov 17. PMID: 33229033
  • Scott K, Phan TT, West AP, Taniguchi CM, Dantzer R. Neutralizing interleukin-6 in tumor-bearing mice does not abrogate behavioral fatigue induced by Lewis lung carcinoma. Behavioural brain research. 2022 Jan 24;417:113607. Epub 2021 Sep 25. PMID: 34571117
  • Barr J, Walz A, Restaino AC, Amit M, Barclay SM, Vichaya EG, Spanos WC, Dantzer R, Talbot S, Vermeer PD. Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer. bioRxiv : the preprint server for biology. 2024 Mar 28. PMID: 37905135
  • Khandaker GM, Dantzer R, Jones PB. Immunopsychiatry: important facts. Psychological medicine. 2017 Oct;47(13):2229-2237. Epub 2017 Apr 18. PMID: 28418288
  • Dantzer R. Psychoneuroendocrinology in 2022. Psychoneuroendocrinology. 2022 Sep;143:105865. Epub 2022 Jul 8. PMID: 35839601
  • Vichaya EG, Molkentine JM, Vermeer DW, Walker AK, Feng R, Holder G, Luu K, Mason RM, Saligan L, Heijnen CJ, Kavelaars A, Mason KA, Lee JH, Dantzer R. Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression. Behavioural brain research. 2016 Jan 15;297:241-50. Epub 2015 Oct 22. PMID: 26475509
  • Prossin A, Koch A, Campbell P, Laumet G, Stohler CS, Dantzer R, Zubieta JK. Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission. Molecular psychiatry. 2022 Feb;27(2):831-839. Epub 2021 Oct 29. PMID: 34716408
  • Hunt C, Macedo E Cordeiro T, Suchting R, de Dios C, Cuellar Leal VA, Soares JC, Dantzer R, Teixeira AL, Selvaraj S. Effect of immune activation on the kynurenine pathway and depression symptoms - A systematic review and meta-analysis. Neuroscience and biobehavioral reviews. 2020 Nov;118:514-523. Epub 2020 Aug 24. PMID: 32853625
  • Scott K, Boukelmoune N, Taniguchi C, West AP, Heijnen CJ, Dantzer R. Resolution of cisplatin-induced fatigue does not require endogenous interleukin-10 in male mice. Behavioural brain research. 2023 Apr 27;444:114381. Epub 2023 Mar 3. PMID: 36870396
  • Belov V, Erwin-Grabner T, Aghajani M, Aleman A, Amod AR, Basgoze Z, Benedetti F, Besteher B, Bülow R, Ching CRK, Connolly CG, Cullen K, Davey CG, Dima D, Dols A, Evans JW, Fu CHY, Gonul AS, Gotlib IH, Grabe HJ, Groenewold N, Hamilton JP, Harrison BJ, Ho TC, Mwangi B, Jaworska N, Jahanshad N, Klimes-Dougan B, Koopowitz SM, Lancaster T, Li M, Linden DEJ, MacMaster FP, Mehler DMA, Melloni E, Mueller BA, Ojha A, Oudega ML, Penninx BWJH, Poletti S, Pomarol-Clotet E, Portella MJ, Pozzi E, Reneman L, Sacchet MD, Sämann PG, Schrantee A, Sim K, Soares JC, Stein DJ, Thomopoulos SI, Uyar-Demir A, van der Wee NJA, van der Werff SJA, Völzke H, Whittle S, Wittfeld K, Wright MJ, Wu MJ, Yang TT, Zarate C, Veltman DJ, Schmaal L, Thompson PM, Goya-Maldonado R, ENIGMA Major Depressive Disorder working group. Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures. Scientific reports. 2024 Jan 11;14(1):1084. PMID: 38212349
  • Marim FM, Teixeira DC, Queiroz-Junior CM, Valiate BVS, Alves-Filho JC, Cunha TM, Dantzer R, Teixeira MM, Teixeira AL, Costa VV. Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection. Frontiers in immunology. 2021 Jul 15;12:702048. doi: 10.3389/fimmu.2021.702048. eCollection 2021. PMID: 34335614
  • Lacourt TE, Vichaya EG, Escalante C, Manzullo EF, Gunn B, Hess KR, Heijnen CJ, Dantzer R. An effort expenditure perspective on cancer-related fatigue. Psychoneuroendocrinology. 2018 Oct;96:109-117. Epub 2018 Jun 9. PMID: 29929087