Short-term fasting has been shown to provide host protective effects from the toxicity associated with high- dose chemotherapy. We found a novel protective effect conferred by short-term fasting when treating mice with high dose chemotherapy. We demonstrated that fasting mice for 24 h confers protection to small intestinal (SI) stem cells from high-dose etoposide. We also showed increased survival in mice that have been fasted for 24 h prior to treatment with toxic doses of radiation. We will test the hypothesis that the metabolic changes associated with fasting lead to epigenetic changes in SI stem cells, which in turn, leads to expression of genes whose protein products protect SI stem cells from lethal DNA damage. This hypothesis will be tested in fasted mice exposed to high-dose etoposide and mice exposed to high-dose radiation. The clinical applications of our findings will be evaluated in a mouse model of pancreatic cancer.

Public Health Relevance

The studies outlined in this proposal will delineate the molecular mechanisms underlying how fasting protects SI stem cells from high-dose chemotherapy and high-dose radiation therapy (RT) with the goal of mitigating deleterious side effects associated with chemotherapy and RT so that dose escalation regimens can be employed for efficient tumor cell killing.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA207236-03
Application #
9640422
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
2017-03-14
Project End
2022-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
de la Cruz Bonilla, Marimar; Stemler, Kristina M; Taniguchi, Cullen M et al. (2018) Stem cell enriched-epithelial spheroid cultures for rapidly assaying small intestinal radioprotectors and radiosensitizers in vitro. Sci Rep 8:15410