# The Metabolic Basis of Cancer-Related Fatigue

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $399,810

## Abstract

Project Summary – 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.

## Key facts

- **NIH application ID:** 10428565
- **Project number:** 5R01CA193522-08
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Robert Dantzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $399,810
- **Award type:** 5
- **Project period:** 2015-05-19 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428565

## Citation

> US National Institutes of Health, RePORTER application 10428565, The Metabolic Basis of Cancer-Related Fatigue (5R01CA193522-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428565. Licensed CC0.

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