Patients with human papilloma virus (HPV+)-related oropharyngeal squamous cell carcinoma (OPSCC) experience severe systemic symptoms including fatigue, depression, and cognitive dysfunction during the course of cancer therapy. These symptoms negatively affect quality of life and compromise their daily social and vocational functioning, even after cessation of therapy. The long-term goal of this project is to elucidate, using a syngeneic murine model of HPV+ OPSCC exposed to chemoradiation, how the tumor and cancer therapy induce symptoms and what can be done to prevent symptom development. Because of the strong analogy between cancer-related symptoms and the behavioral signs of inflammation-induced sickness, the working hypothesis is that the inflammatory response to HPV+ OPSCC and to cytotoxic therapy propagates to the brain and activates the neuronal circuitry of sickness. This hypothesis will be tested in 3 specific aims designed to: (1) characterize the association between the development of sickness and the time course of peripheral and central inflammation, and determine the status of microglia activation in mice implanted with HPV+ positive tumor cells and exposed to chemoradiation; (2) identify the molecular factors that cause tumor- and chemoradiation-associated sickness by focusing on triggers and mediators of inflammation, including damage-associated molecular patterns (DAMPs) and cytokine signaling pathways; and (3) determine whether activation of the kynurenine pathway downstream of cytokine signaling pathways contributes to the development of chemoradiation-induced sickness. Because the immune system of the host is involved in chemoradiation-induced clearance of OPSCC especially in HPV+ tumors, we will search for druggable targets in the chain of events leading from the release of DAMPs to the recruitment of neuronal circuits of sickness that do not compromise tumor clearance and survival. There is an increasing incidence rate of HPV+ OPSCC that contrasts with steady declines in HPV-OPSCC. HPV+ OPSCC predominantly affects individuals at peak productive points in their lives, with enormous costs to affected individuals and the society. Identification of means to alleviate symptom burden and facilitate the return to normal daily functioning will have an important positive individual and societal impact.

Public Health Relevance

In response to chemotherapy and radiotherapy patients with human papilloma virus-related oropharyngeal squamous cell carcinoma experience high levels of such symptoms as fatigue and depression, for which there is no preventive or curative treatment. In the current proposal we will elucidate the mechanisms of interaction between the immune system and the brain in order to discover new targets for interventions aiming to alleviate symptoms without compromising response of the tumor to cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA193522-01
Application #
8863142
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
O'Mara, Ann M
Project Start
2015-05-19
Project End
2019-04-30
Budget Start
2015-05-19
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lacourt, Tamara E; Vichaya, Elisabeth G; Chiu, Gabriel S et al. (2018) The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Front Behav Neurosci 12:78
Grossberg, Aaron J; Vichaya, Elisabeth G; Christian, Diana L et al. (2018) Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling. Cancer Res 78:695-705
Meier, Timothy B; Drevets, Wayne C; Teague, T Kent et al. (2018) Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression. Brain Behav Immun 67:59-64
Lacourt, Tamara E; Vichaya, Elisabeth G; Escalante, Carmen et al. (2018) An effort expenditure perspective on cancer-related fatigue. Psychoneuroendocrinology 96:109-117
Vichaya, Elisabeth G; Dantzer, Robert (2018) Inflammation-induced motivational changes: Perspective gained by evaluating positive and negative valence systems. Curr Opin Behav Sci 22:90-95
Dantzer, Robert (2018) Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol Rev 98:477-504
Colpo, Gabriela D; Leboyer, Marion; Dantzer, Robert et al. (2018) Immune-based strategies for mood disorders: facts and challenges. Expert Rev Neurother 18:139-152
Vichaya, Elisabeth G; Vermeer, Daniel W; Christian, Diana L et al. (2017) Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer. Psychoneuroendocrinology 79:59-66
Khandaker, G M; Dantzer, R; Jones, P B (2017) Immunopsychiatry: important facts. Psychol Med 47:2229-2237
Maj, Magdalena A; Ma, Jiacheng; Krukowski, Karen N et al. (2017) Inhibition of Mitochondrial p53 Accumulation by PFT-? Prevents Cisplatin-Induced Peripheral Neuropathy. Front Mol Neurosci 10:108

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